Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Masato Akiyama Last modified date:2021.11.25

Lecturer / Faculty of Medical Sciences


Papers
1. Asahi Hishida, Masahiro Nakatochi, Masato Akiyama, Yoichiro Kamatani, Takeshi Nishiyama, Hidemi Ito, Isao Oze, Yuichiro Nishida, Megumi Hara, Naoyuki Takashima, Tanvir Chowdhury Turin, Miki Watanabe, Sadao Suzuki, Rie Ibusuki, Ippei Shimoshikiryo, Yohko Nakamura, Haruo Mikami, Hiroaki Ikezaki, Norihiro Furusyo, Kiyonori Kuriki, Kaori Endoh, Teruhide Koyama, Daisuke Matsui, Hirokazu Uemura, Kokichi Arisawa, Tae Sasakabe, Rieko Okada, Sayo Kawai, Mariko Naito, Yukihide Momozawa, Michiaki Kubo, Kenji Wakai, Genome-Wide Association Study of Renal Function Traits: Results from the Japan Multi-Institutional Collaborative Cohort Study., American journal of nephrology, 10.1159/000488946, 47, 5, 304-316, 2018.05, BACKGROUND: Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide. METHODS: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects. RESULTS: In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of -activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10-6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10-8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations. CONCLUSION: Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations..
2. Masahiro Nakatochi, Masahiro Kanai, Akiyoshi Nakayama, Asahi Hishida, Yusuke Kawamura, Sahoko Ichihara, Masato Akiyama, Hiroaki Ikezaki, Norihiro Furusyo, Seiko Shimizu, Ken Yamamoto, Makoto Hirata, Rieko Okada, Sayo Kawai, Makoto Kawaguchi, Yuichiro Nishida, Chisato Shimanoe, Rie Ibusuki, Toshiro Takezaki, Mayuko Nakajima, Mikiya Takao, Etsuko Ozaki, Daisuke Matsui, Takeshi Nishiyama, Sadao Suzuki, Naoyuki Takashima, Yoshikuni Kita, Kaori Endoh, Kiyonori Kuriki, Hirokazu Uemura, Kokichi Arisawa, Isao Oze, Keitaro Matsuo, Yohko Nakamura, Haruo Mikami, Takashi Tamura, Hiroshi Nakashima, Takahiro Nakamura, Norihiro Kato, Koichi Matsuda, Yoshinori Murakami, Tatsuaki Matsubara, Mariko Naito, Michiaki Kubo, Yoichiro Kamatani, Nariyoshi Shinomiya, Mitsuhiro Yokota, Kenji Wakai, Yukinori Okada, Hirotaka Matsuo, Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals., Communications biology, 10.1038/s42003-019-0339-0, 2, 115-115, 2019.04, Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10-8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci-TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A-are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout..
3. Jun Funatsu, Yusuke Murakami, Shunji Nakatake, Masato Akiyama, Kohta Fujiwara, Shotaro Shimokawa, Takashi Tachibana, Toshio Hisatomi, Yoshito Koyanagi, Yukihide Momozawa, Koh-Hei Sonoda, Yasuhiro Ikeda, Direct comparison of retinal structure and function in retinitis pigmentosa by co-registering microperimetry and optical coherence tomography., PloS one, 10.1371/journal.pone.0226097, 14, 12, e0226097, 2019.12, PURPOSE: To evaluate the retinal structure-function relationships in the macula of retinitis pigmentosa (RP) patients by comparing microperimetry-3 (MP-3) images with co-registered optical coherence tomography (OCT) images. METHODS: Thirty patients with typical RP were recruited from our hospital. The maculae of patients were examined with MP-3 and OCT. The retinal sensitivity was measured by MP-3 at 40 testing points arranged concentrically in a 16° diameter of the central retina, and we divided the 40 points into four zones according to degree from the fovea (2°, 4°, 6°, and 8°). We analyzed the correlation coefficients between the retinal sensitivity and the total retinal thickness (TRT), the length from the inner limiting membrane to the retinal pigment epithelium (RPE), and between the retinal sensitivity and the outer retinal thickness (ORT), the length from the outer plexiform layer to the RPE at each stimulus point. RESULTS: TRT showed moderate correlations with the retinal sensitivity at 2° (median ρ = 0.59 interquartile range (IQR) [0.38-0.72]), 4° (ρ = 0.59 [0.55-0.68]) and 6° (ρ = 0.60 [0.54-0.63]), and TRT was weakly-to-moderately related to the retinal sensitivity at 8° (ρ = 0.27 [0.19-0.48]). ORT exhibited strong correlations at 2° (ρ = 0.72 [0.60-0.81]), 4° (ρ = 0.71 [0.75-0.67]) and 6° (ρ = 0.70 [0.54-0.74]), and a weak-to-moderate correlations at 8° (ρ = 0.34 [0.29-0.53]). ORT was more strongly correlated with the retinal sensitivity compared to TRT (p = 0.018). CONCLUSION: ORT, rather than TRT, within 6° eccentricity was strongly correlated with the retinal sensitivity, suggesting that measuring ORT in those areas will help evaluate the macular status and progression in RP..
4. Mitsuru Arima, Masato Akiyama, Kohta Fujiwara, Yujiro Mori, Hirosuke Inoue, Eiko Seki, Takahito Nakama, Shoko Tsukamoto, Masayuki Ochiai, Shouichi Ohga, Koh-Hei Sonoda, Neurodevelopmental outcomes following intravitreal bevacizumab injection in Japanese preterm infants with type 1 retinopathy of prematurity., PloS one, 10.1371/journal.pone.0230678, 15, 3, e0230678, 2020.03, PURPOSE: The purpose of this study was to evaluate neurodevelopmental outcomes in 18-month old (corrected age) preterm infants who received an intravitreal bevacizumab (IVB) injection for the treatment of type 1 retinopathy of prematurity (ROP). METHODS: In this ten-year retrospective study, we reviewed the medical records of patients who underwent ROP screening at Kyushu University Hospital. Among the patients who received IVB or laser photocoagulation (LPC) for the treatment of type 1 ROP, we included infants whose neurodevelopmental examination (the Kyoto Scale of Psychological Development [KSPD]) results at 18 months corrected age were available. Then, the effect of IVB on the developmental quotient (DQ) in each KSPD domain (Postural-Movement, Cognitive-Adaptive, or Language-Social domain) or the overall DQ was investigated by performing linear regression analysis. RESULTS: Out of the 513 patients reviewed, 53 were included in the study. IVB and LPC were performed for 14 and 39 patients, respectively. Administration of IVB was significantly associated with neurodevelopmental delay in the Language-Social domain (p = 0.01). The observed association remained even after adjusting for gestational age and birth weight (p = 0.03). CONCLUSIONS: Administration of IVB may introduce a risk of developmental impairment of interpersonal relationships, socializations, and/or verbal abilities of preterm children. We recommended that preterm infants who received IVB undergo a neurodevelopmental reassessment during their school years or in adulthood..
5. Kenichiro Mori, Keijiro Ishikawa, Iori Wada, Yuki Kubo, Yoshiyuki Kobayashi, Takahito Nakama, Masatoshi Haruta, Masato Akiyama, Shintaro Nakao, Shigeo Yoshida, Koh-Hei Sonoda, Changes in metamorphopsia after the treat-and-extend regimen of anti-VEGF therapy for macular edema associated with branch retinal vein occlusion., PloS one, 10.1371/journal.pone.0241343, 15, 10, e0241343, 2020.10, This study aims to investigate the changes in metamorphopsia after administering the treat-and-extend regimen of anti-vascular endothelial growth factor therapy for branch retinal vein occlusion-associated macular edema. We retrospectively examined 27 patients (27 eyes) with macula edema due to branch retinal vein occlusion who received intravitreal injections of anti-vascular endothelial growth factor agents using the treat-and-extend regimen for ≥18 months. We evaluated best-corrected visual acuity, central macular thickness, macular edema recurrence, and amount of metamorphopsia quantified by M-CHARTS. The best-corrected visual acuity (logarithm of minimum angle of resolution) and central macular thickness significantly improved at 18 months compared to baseline, the median value (interquartile range [IQR]), 0.30 (0.15-0.52) and 459 (373-542) μm at baseline, and 0 (-0.08-0.16) and 267 (232-306) μm at 18 months. The M-CHARTS score (the mean of vertical and horizontal scores) significantly decreased at 1, 6, and 12 months compared to baseline, but worsened at 18 month, the median value (IQR), 0.45 (0.250-0.925), 0.4 (0.15-0.70), 0.4 (0.150-0.625), 0.4 (0.225-0.550) and 0.45 (0.225-0.750) at baseline, 1 month, 6 months, 12 months and 18 months, respectively. The median cumulative number of macular edema recurrences was 2 (IQR, 0.5-3.0) at 18 months. Simple linear regression and multivariate analyses revealed that the change in the mean M-CHARTS score at 18 months was significantly correlated with the baseline score and the cumulative number of macular edema recurrences. Anti-vascular endothelial growth factor therapy using the treat-and-extend regimen improved metamorphopsia in branch retinal vein occlusion-related macular edema in the short to mid-term follow-up period, but not in the long term. Macular edema recurrence may be associated with persistent metamorphopsia..
6. Shoji Notomi, Satomi Shiose, Keijiro Ishikawa, Yosuke Fukuda, Kumiko Kano, Kenichiro Mori, Iori Wada, Yoshihiro Kaizu, Hidetaka Matsumoto, Masato Akiyama, Koh-Hei Sonoda, Drusen and pigment abnormality predict the development of neovascular age-related macular degeneration in Japanese patients., PloS one, 10.1371/journal.pone.0255213, 16, 7, e0255213, 2021.07, Drusen are known to be the important hallmark to predict the development of age-related macular degeneration (AMD). The prevalence of drusen is lower in Asians compared with Caucasians so that the role of signs constituting early AMD is not well established in Asian populations as in Western countries. In this study, we retrospectively investigated clinical characteristics and 5-year incidence of neovascular AMD (nAMD) in the fellow eye of unilateral nAMD patients. Of 296 consecutive unilateral nAMD patients who had been followed up more than 5 years, 170 typical AMD, 119 polypoidal choroidal vasculopathy, and 7 retinal angiomatous proliferation were included. To examine factors associated with nAMD occurrence in the fellow eye, drusen and pigmentary abnormality in the fellow eye were classified into 4 categories; Category 1: no or small drusen < 63 μm (37.2%), Category 2: 63-125 μm medium drusen or pigmentary abnormality (22.2%), Category 3: large drusen > 125 μm (25.0%), Category P: pachydrusen (15.5%). The mean sub-foveal choroidal thickness (SFCT) was Category 1: 276 μm, Category 2: 308 μm, Category 3: 246 μm, and Category P: 302 μm, respectively. Of note, SFCT in Category 2 and Category P was significantly larger than those of Category 3. Finally, the 5-year incidence of nAMD in the fellow eye was 32/296 (10.8%); Category 1: 0/110 (0%), Category 2: 12/66 (18.2%), Category 3: 20/74 (27.0%), and Category P: 0/46 (0%). Thus, signs of intermediate AMD (large drusen) as well as those of early AMD, especially the pigmentary abnormality, may contribute to development of bilateral nAMD in Japanese patients..
7. Masato Akiyama, Yasuhiro Ikeda, Noriko Yoshida, Shoji Notomi, Yusuke Murakami, Toshio Hisatomi, Hiroshi Enaida, Tatsuro Ishibashi, Therapeutic efficacy of topical unoprostone isopropyl in retinitis pigmentosa., Acta ophthalmologica, 92, 3, e229-34, 2014.05, PURPOSE: To evaluate the therapeutic effect of topical unoprostone isopropyl (unoprostone) on patients with retinitis pigmentosa (RP). METHODS: Forty patients with typical forms of RP were included in the study.Seventeen of 40 patients were treated with 0.12% topical unoprostone twice daily in a randomly selected eye. Patients underwent follow-up examinations every 3 months after treatment. The efficacy of the treatment was monitored by visual acuity and visual field measurement testing using the Humphrey Field Analyzer (HFA: the central 10-2 programme). Moreover, 12 RP patients who were included this study and 12 normal subjects were evaluated in terms of their macular blood flow of both eyes after instillation of unoprostone using the laser speckle method. RESULTS: One year after treatment, the 'macular sensitivity', calculated by HFA as the average sensitivity of the central 12 points, was preserved in the fellow eyes as well as the unoprostone-treated eyes. On the other hand, that in the eyes of the control RP patient was significantly decreased. Moreover, there were significantly greater improvements of the 'macular sensitivity' in the unoprostone-treated eyes than the fellow eyes. The change ratios of macular blood flow obtained from both RP patients and normal subjects were significantly increased in both the treated and the fellow eyes. No severe side-effects were observed. CONCLUSIONS: These results demonstrate that topical unoprostone might have a therapeutic efficacy in patients with RP as a consequence of the macular bloodflow improvement as well as its direct neuroprotective effect..
8. Yusuke Murakami, Yasuhiro Ikeda, Masato Akiyama, Kota Fujiwara, Noriko Yoshida, Shunji Nakatake, Shoji Notomi, Takahiro Nabeshima, Toshio Hisatomi, Hiroshi Enaida, Tatsuro Ishibashi, Correlation between macular blood flow and central visual sensitivity in retinitis pigmentosa., Acta ophthalmologica, 10.1111/aos.12693, 93, 8, e644-8, 2015.12, PURPOSE: To investigate the changes in macular blood flow and the correlation between those changes and central visual function in patients with retinitis pigmentosa (RP). METHODS: The mean blur rate (MBR), a quantitative blurring index of the laser speckle pattern that represents retinal and choroidal blood flow, was measured by laser speckle flowgraphy. Mean blur rate values in the macular area were compared between 70 patients with RP and 28 control subjects. The relationships between MBR on the one hand and, on the other, visual acuity (VA), mean deviation (MD) and averaged macular sensitivity of static perimetry tests (Humphrey Filed Analyzer, the central 10-2 program) were analysed in patients with RP. RESULTS: Macular MBR was decreased to 75% in patients with RP compared with control subjects (p < 0.0001, Student's t-test). Spearman's rank testing showed that macular MBR was significantly correlated with VA (r = -0.261, p = 0.0299), MD values (r = 0.438, p = 0.0002) and averaged macular sensitivity at the central 4 and 12 points of static perimetry tests (r = 0.426 and 0.442, p = 0.0003 and 0.0002, respectively). Multivariable-adjusted analysis confirmed that MBR was independently associated with MD (p = 0.0002) and macular sensitivity at the central 4 and 12 points (p < 0.0001 and 0.0002, respectively). CONCLUSIONS: Decreased macular blood flow was associated with reduced macular visual sensitivity in patients with RP. Although the cause-effect relationships remain to be elucidated, these findings suggest that vascular defects may be involved in the pathogenesis of RP such as central vision loss..
9. Yukihide Momozawa, Masato Akiyama, Yoichiro Kamatani, Satoshi Arakawa, Miho Yasuda, Shigeo Yoshida, Yuji Oshima, Ryusaburo Mori, Koji Tanaka, Keisuke Mori, Satoshi Inoue, Hiroko Terasaki, Tetsuhiro Yasuma, Shigeru Honda, Akiko Miki, Maiko Inoue, Kimihiko Fujisawa, Kanji Takahashi, Tsutomu Yasukawa, Yasuo Yanagi, Kazuaki Kadonosono, Koh-Hei Sonoda, Tatsuro Ishibashi, Atsushi Takahashi, Michiaki Kubo, Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population., Human molecular genetics, 10.1093/hmg/ddw335, 25, 22, 5027-5034, 2016.11, Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Previous sequencing studies of AMD susceptibility genes have revealed the association of rare coding variants in CFH, CFI, C3 and C9 in European population; however, the impact of rare or low-frequency coding variants on AMD susceptibility in other populations is largely unknown. To identify the role of low-frequency coding variants on exudative AMD susceptibility in a Japanese population, we analysed the association of coding variants of 34 AMD candidate genes in the two-stage design by a multiplex PCR-based target sequencing method. We used a total of 2,886 (1st: 827, 2nd: 2,059) exudative AMD cases including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation and 9,337 (1st: 3,247 2nd: 6,090) controls. Gene-based analysis found a significant association of low-frequency variants (minor allele frequency (MAF) < 0.05) in CETP, C2 and CFB. The association of CETP remained after conditioned with all known genome-wide association study (GWAS) associated variants. In addition, when we included only disruptive variants, enrichment of rare variants (MAF < 0.01) was also observed after conditioned with all GWAS associated variants (P = 1.03 × 10−6, odds ratio (OR) = 2.48). Haplotype and conditional analysis of the C2-CFB-SKIV2L locus showed a low-frequency variant (R74H) in CFB would be individually associated with AMD susceptibility independent of the GWAS associated SNP. These findings highlight the importance of target sequencing to reveal the impact of rare or low-frequency coding variants on disease susceptibility in different ethnic populations..
10. Yukinori Okada, Akari Suzuki, Katsunori Ikari, Chikashi Terao, Yuta Kochi, Koichiro Ohmura, Koichiro Higasa, Masato Akiyama, Kyota Ashikawa, Masahiro Kanai, Jun Hirata, Naomasa Suita, Yik-Ying Teo, Huji Xu, Sang-Cheol Bae, Atsushi Takahashi, Yukihide Momozawa, Koichi Matsuda, Shigeki Momohara, Atsuo Taniguchi, Ryo Yamada, Tsuneyo Mimori, Michiaki Kubo, Matthew A Brown, Soumya Raychaudhuri, Fumihiko Matsuda, Hisashi Yamanaka, Yoichiro Kamatani, Kazuhiko Yamamoto, Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis., American journal of human genetics, 10.1016/j.ajhg.2016.06.019, 99, 2, 366-74, 2016.08, Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping..
11. Masato Akiyama, Yukinori Okada, Masahiro Kanai, Atsushi Takahashi, Yukihide Momozawa, Masashi Ikeda, Nakao Iwata, Shiro Ikegawa, Makoto Hirata, Koichi Matsuda, Motoki Iwasaki, Taiki Yamaji, Norie Sawada, Tsuyoshi Hachiya, Kozo Tanno, Atsushi Shimizu, Atsushi Hozawa, Naoko Minegishi, Shoichiro Tsugane, Masayuki Yamamoto, Michiaki Kubo, Yoichiro Kamatani, Genome-wide association study identifies 112 new loci for body mass index in the Japanese population., Nature genetics, 10.1038/ng.3951, 49, 10, 1458-1467, 2017.10, Obesity is a risk factor for a wide variety of health problems. In a genome-wide association study (GWAS) of body mass index (BMI) in Japanese people (n = 173,430), we found 85 loci significantly associated with obesity (P < 5.0 × 10-8), of which 51 were previously unknown. We conducted trans-ancestral meta-analyses by integrating these results with the results from a GWAS of Europeans and identified 61 additional new loci. In total, this study identifies 112 novel loci, doubling the number of previously known BMI-associated loci. By annotating associated variants with cell-type-specific regulatory marks, we found enrichment of variants in CD19+ cells. We also found significant genetic correlations between BMI and lymphocyte count (P = 6.46 × 10-5, rg = 0.18) and between BMI and multiple complex diseases. These findings provide genetic evidence that lymphocytes are relevant to body weight regulation and offer insights into the pathogenesis of obesity..
12. Paisan Ruamviboonsuk, Mongkol Tadarati, Panisa Singhanetr, Sukanya Wattanapokayakit, Punna Kunhapan, Thanyapat Wanitchanon, Nuanjun Wichukchinda, Taisei Mushiroda, Masato Akiyama, Yukihide Momozawa, Michiaki Kubo, Surakameth Mahasirimongkol, Genome-wide association study of neovascular age-related macular degeneration in the Thai population., Journal of human genetics, 10.1038/jhg.2017.72, 62, 11, 957-962, 2017.11, We performed a genome-wide association study on 377 cases of neovascular age-related macular degeneration (AMD) and 1074 controls to determine the association of previously reported genetic variants associated with neovascular AMD in the Thai population. All patients were of Thai ancestry. We confirmed the association of age-related maculopathy susceptibility 2 (ARMS2) rs10490924 (P=7.38 × 10-17), HTRA1 rs11200638 (P=5.47 × 10-17) and complement factor H gene (CFH) rs800292 (P=2.53 × 10-8) with neovascular AMD, all loci passing the genome-wide significance level (P<5.22 × 10-8). We also found association of the previously reported CFH rs10737680 (P=1.76 × 10-6) locus in the discovery sample. Two loci not previously reported to be associated with neovascular AMD were selected for replication in 222 cases and 623 controls. The loci included LINCO1317 rs6733379 and rs2384550 on chromosome 12. LINCO1317 rs6733379 (P=3.85 × 10-2) remained significantly associated with neovascular AMD after replication. In conclusion, we confirm that ARMS2, HTRA1 and CFH variants are associated with neovascular AMD in the Thai population. Findings from this study also suggest that variants contributing to the susceptibility of neovascular AMD in the Thai population are mostly similar to other Asians with additional local genetic risks that may specifically be identified in Thai population..
13. Yuma Sakamoto, Takuaki Yamamoto, Nobuhiko Sugano, Daisuke Takahashi, Toshiyuki Watanabe, Takashi Atsumi, Junichi Nakamura, Yukiharu Hasegawa, Koichi Akashi, Ichiei Narita, Takeshi Miyamoto, Tsutomu Takeuchi, Katsunori Ikari, Koichi Amano, Atsuhiro Fujie, Toshikazu Kubo, Yoshifumi Tada, Ayumi Kaneuji, Hiroaki Nakamura, Tomoya Miyamura, Tamon Kabata, Ken Yamaji, Takahiro Okawa, Akihiro Sudo, Kenji Ohzono, Yoshiya Tanaka, Yuji Yasunaga, Shuichi Matsuda, Yuuki Imai, Masato Akiyama, Michiaki Kubo, Yoichiro Kamatani, Yukihide Iwamoto, Shiro Ikegawa, Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head., Scientific reports, 10.1038/s41598-017-14778-y, 7, 1, 15035-15035, 2017.11, Idiopathic osteonecrosis of the femoral head (IONFH) is an ischemic disorder that causes bone necrosis of the femoral head, resulting in hip joint dysfunction. IONFH is a polygenic disease and steroid and alcohol have already known to increase its risk; however, the mechanism of IONFH remains to be elucidated. We performed a genome-wide association study using ~60,000 subjects and found two novel loci on chromosome 20q12 and 12q24. Big data analyses identified LINC01370 as a candidate susceptibility gene in the 20q12 locus. Stratified analysis by IONFH risk factors suggested that the 12q24 locus was associated with IONFH through drinking capacity. Our findings would shed new light on pathophysiology of IONFH..
14. Yoshito Koyanagi, Yusuke Murakami, Jun Funatsu, Masato Akiyama, Shunji Nakatake, Kohta Fujiwara, Takashi Tachibana, Shintaro Nakao, Toshio Hisatomi, Shigeo Yoshida, Tatsuro Ishibashi, Koh-Hei Sonoda, Yasuhiro Ikeda, Optical coherence tomography angiography of the macular microvasculature changes in retinitis pigmentosa., Acta ophthalmologica, 10.1111/aos.13475, 96, 1, e59-e67, 2018.02, PURPOSE: To investigate the macular microvasculature changes by optical coherence tomography angiography (OCTA) and analyse the correlation between these changes and central visual function in patients with retinitis pigmentosa (RP). METHODS: We measured the area of the foveal avascular zone (FAZ) and the foveal and parafoveal flow density (FFD and PFD, respectively) in the superficial (S) and deep (D) retinal plexus by OCTA (AngioVue) and compared these values between 73 RP patients and 36 healthy controls. We analysed the relationships between these microvasculature measurements and central visual functions such as visual acuity (VA) and the values of static perimetry tests (Humphrey Field Analyzer, the central 10-2 program) in the RP patients. RESULTS: The FFD-S, PFD-S and PFD-D were significantly decreased in the RP patients compared to the controls (all p < 0.05), whereas there was no significant difference in the FAZ-S, FAZ-D or FFD-D (all p > 0.05). A subgroup analysis showed that the RP patients with VA <20/20 had increased FAZ-S compared to the controls and RP patients with VA ≥20/20 (p = 0.01 and p = 0.007, respectively). Spearman rank testing demonstrated that PFD-S and PFD-D were significantly correlated with all of the central visual parameters (all p < 0.01). The FAZ-S and FFD-S were significantly correlated with VA, and FAZ-D and FFD-D showed no significant correlation. CONCLUSION: Both the superficial and deep layers of the parafoveal microvasculature are attenuated in RP and correlated with reduced central visual function. The foveal microvasculature, especially in the deep layer, was relatively preserved until mild-to-moderately advanced stages..
15. Fumihiko Takeuchi, Masato Akiyama, Nana Matoba, Tomohiro Katsuya, Masahiro Nakatochi, Yasuharu Tabara, Akira Narita, Woei-Yuh Saw, Sanghoon Moon, Cassandra N Spracklen, Jin-Fang Chai, Young-Jin Kim, Liang Zhang, Chaolong Wang, Huaixing Li, Honglan Li, Jer-Yuarn Wu, Rajkumar Dorajoo, Jovia L Nierenberg, Ya Xing Wang, Jing He, Derrick A Bennett, Atsushi Takahashi, Yukihide Momozawa, Makoto Hirata, Koichi Matsuda, Hiromi Rakugi, Eitaro Nakashima, Masato Isono, Matsuyuki Shirota, Atsushi Hozawa, Sahoko Ichihara, Tatsuaki Matsubara, Ken Yamamoto, Katsuhiko Kohara, Michiya Igase, Sohee Han, Penny Gordon-Larsen, Wei Huang, Nanette R Lee, Linda S Adair, Mi Yeong Hwang, Juyoung Lee, Miao Li Chee, Charumathi Sabanayagam, Wanting Zhao, Jianjun Liu, Dermot F Reilly, Liang Sun, Shaofeng Huo, Todd L Edwards, Jirong Long, Li-Ching Chang, Chien-Hsiun Chen, Jian-Min Yuan, Woon-Puay Koh, Yechiel Friedlander, Tanika N Kelly, Wen Bin Wei, Liang Xu, Hui Cai, Yong-Bing Xiang, Kuang Lin, Robert Clarke, Robin G Walters, Iona Y Millwood, Liming Li, John C Chambers, Jaspal S Kooner, Paul Elliott, Pim van der Harst, Zhengming Chen, Makoto Sasaki, Xiao-Ou Shu, Jost B Jonas, Jiang He, Chew-Kiat Heng, Yuan-Tsong Chen, Wei Zheng, Xu Lin, Yik-Ying Teo, E-Shyong Tai, Ching-Yu Cheng, Tien Yin Wong, Xueling Sim, Karen L Mohlke, Masayuki Yamamoto, Bong-Jo Kim, Tetsuro Miki, Toru Nabika, Mitsuhiro Yokota, Yoichiro Kamatani, Michiaki Kubo, Norihiro Kato, Interethnic analyses of blood pressure loci in populations of East Asian and European descent., Nature communications, 10.1038/s41467-018-07345-0, 9, 1, 5052-5052, 2018.11, Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP..
16. Saori Sakaue, Jun Hirata, Yuichi Maeda, Eiryo Kawakami, Takuro Nii, Toshihiro Kishikawa, Kazuyoshi Ishigaki, Chikashi Terao, Ken Suzuki, Masato Akiyama, Naomasa Suita, Tatsuo Masuda, Kotaro Ogawa, Kenichi Yamamoto, Yukihiko Saeki, Masato Matsushita, Maiko Yoshimura, Hidetoshi Matsuoka, Katsunori Ikari, Atsuo Taniguchi, Hisashi Yamanaka, Hideya Kawaji, Timo Lassmann, Masayoshi Itoh, Hiroyuki Yoshitomi, Hiromu Ito, Koichiro Ohmura, Alistair R R Forrest, Yoshihide Hayashizaki, Piero Carninci, Atsushi Kumanogoh, Yoichiro Kamatani, Michiel de Hoon, Kazuhiko Yamamoto, Yukinori Okada, Integration of genetics and miRNA-target gene network identified disease biology implicated in tissue specificity., Nucleic acids research, 10.1093/nar/gky1066, 46, 22, 11898-11909, 2018.12, MicroRNAs (miRNAs) modulate the post-transcriptional regulation of target genes and are related to biology of complex human traits, but genetic landscape of miRNAs remains largely unknown. Given the strikingly tissue-specific miRNA expression profiles, we here expand a previous method to quantitatively evaluate enrichment of genome-wide association study (GWAS) signals on miRNA-target gene networks (MIGWAS) to further estimate tissue-specific enrichment. Our approach integrates tissue-specific expression profiles of miRNAs (∼1800 miRNAs in 179 cells) with GWAS to test whether polygenic signals enrich in miRNA-target gene networks and whether they fall within specific tissues. We applied MIGWAS to 49 GWASs (nTotal = 3 520 246), and successfully identified biologically relevant tissues. Further, MIGWAS could point miRNAs as candidate biomarkers of the trait. As an illustrative example, we performed differentially expressed miRNA analysis between rheumatoid arthritis (RA) patients and healthy controls (n = 63). We identified novel biomarker miRNAs (e.g. hsa-miR-762) by integrating differentially expressed miRNAs with MIGWAS results for RA, as well as novel associated loci with significant genetic risk (rs56656810 at MIR762 at 16q11; n = 91 482, P = 3.6 × 10-8). Our result highlighted that miRNA-target gene network contributes to human disease genetics in a cell type-specific manner, which could yield an efficient screening of miRNAs as promising biomarkers..
17. Yukihiro Shiga, Masato Akiyama, Koji M Nishiguchi, Kota Sato, Nobuhiro Shimozawa, Atsushi Takahashi, Yukihide Momozawa, Makoto Hirata, Koichi Matsuda, Taiki Yamaji, Motoki Iwasaki, Shoichiro Tsugane, Isao Oze, Haruo Mikami, Mariko Naito, Kenji Wakai, Munemitsu Yoshikawa, Masahiro Miyake, Kenji Yamashiro, Kenji Kashiwagi, Takeshi Iwata, Fumihiko Mabuchi, Mitsuko Takamoto, Mineo Ozaki, Kazuhide Kawase, Makoto Aihara, Makoto Araie, Tetsuya Yamamoto, Yoshiaki Kiuchi, Makoto Nakamura, Yasuhiro Ikeda, Koh-Hei Sonoda, Tatsuro Ishibashi, Koji Nitta, Aiko Iwase, Shiroaki Shirato, Yoshitaka Oka, Mamoru Satoh, Makoto Sasaki, Nobuo Fuse, Yoichi Suzuki, Ching-Yu Cheng, Chiea Chuen Khor, Mani Baskaran, Shamira Perera, Tin Aung, Eranga N Vithana, Jessica N Cooke Bailey, Jae H Kang, Louis R Pasquale, Jonathan L Haines, Janey L Wiggs, Kathryn P Burdon, Puya Gharahkhani, Alex W Hewitt, David A Mackey, Stuart MacGregor, Jamie E Craig, R Rand Allingham, Micheal Hauser, Adeyinka Ashaye, Donald L Budenz, Stephan Akafo, Susan E I Williams, Yoichiro Kamatani, Toru Nakazawa, Michiaki Kubo, Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma., Human molecular genetics, 10.1093/hmg/ddy053, 27, 8, 1486-1496, 2018.04, Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians..
18. Masato Akiyama, Atsushi Takahashi, Yukihide Momozawa, Satoshi Arakawa, Fuyuki Miya, Tatsuhiko Tsunoda, Kyota Ashikawa, Yuji Oshima, Miho Yasuda, Shigeo Yoshida, Hiroshi Enaida, Xue Tan, Yasuo Yanagi, Tsutomu Yasukawa, Yuichiro Ogura, Yoshimi Nagai, Kanji Takahashi, Kimihiko Fujisawa, Maiko Inoue, Akira Arakawa, Koji Tanaka, Mitsuko Yuzawa, Kazuaki Kadonosono, Koh-Hei Sonoda, Tatsuro Ishibashi, Michiaki Kubo, Genome-wide association study suggests four variants influencing outcomes with ranibizumab therapy in exudative age-related macular degeneration., Journal of human genetics, 10.1038/s10038-018-0493-0, 63, 10, 1083-1091, 2018.10, To identify factors associated with ranibizumab responses in patients with exudative age-related macular degeneration (AMD), we performed a genome-wide association study (GWAS) and a replication study using a total of 919 exudative AMD patients treated with intravitreal ranibizumab in a Japanese population. In the combined analysis of GWAS and the replication study, no loci reached genome-wide significant level; however, we found four variants showed suggestive level of associations with visual loss at month three (rs17822656, rs76150532, rs17296444, and rs75165563: Pcombined < 1.0 × 10-5). Of the candidate genes within these loci, three were relevant to VEGF-related pathway (KCNMA1, SOCS2, and OTX2). The proportions of patients who worsened visual acuity were 13.7%, 38.8%, 58.0%, and 80.0% in patients with 0, 1, 2, and 3 or more identified risk variants, respectively. Changes in visual acuity decreased linearly as the number of risk variants increased (P = 1.67 × 10-12). The area under the curve using age, baseline visual acuity, and history of previous treatment was 0.607, and improved significantly to 0.713 in combination with identified variants (P < 0.0001). Although further study is needed to confirm their associations, our results offer candidate variants influencing response to ranibizumab therapy..
19. Alexander Teumer, Layal Chaker, Stefan Groeneweg, Yong Li, Celia Di Munno, Caterina Barbieri, Ulla T Schultheiss, Michela Traglia, Tarunveer S Ahluwalia, Masato Akiyama, Emil Vincent R Appel, Dan E Arking, Alice Arnold, Arne Astrup, Marian Beekman, John P Beilby, Sofie Bekaert, Eric Boerwinkle, Suzanne J Brown, Marc De Buyzere, Purdey J Campbell, Graziano Ceresini, Charlotte Cerqueira, Francesco Cucca, Ian J Deary, Joris Deelen, Kai-Uwe Eckardt, Arif B Ekici, Johan G Eriksson, Luigi Ferrrucci, Tom Fiers, Edoardo Fiorillo, Ian Ford, Caroline S Fox, Christian Fuchsberger, Tessel E Galesloot, Christian Gieger, Martin Gögele, Alessandro De Grandi, Niels Grarup, Karin Halina Greiser, Kadri Haljas, Torben Hansen, Sarah E Harris, Diana van Heemst, Martin den Heijer, Andrew A Hicks, Wouter den Hollander, Georg Homuth, Jennie Hui, M Arfan Ikram, Till Ittermann, Richard A Jensen, Jiaojiao Jing, J Wouter Jukema, Eero Kajantie, Yoichiro Kamatani, Elisa Kasbohm, Jean-Marc Kaufman, Lambertus A Kiemeney, Margreet Kloppenburg, Florian Kronenberg, Michiaki Kubo, Jari Lahti, Bruno Lapauw, Shuo Li, David C M Liewald, Ee Mun Lim, Allan Linneberg, Michela Marina, Deborah Mascalzoni, Koichi Matsuda, Daniel Medenwald, Christa Meisinger, Ingrid Meulenbelt, Tim De Meyer, Henriette E Meyer Zu Schwabedissen, Rafael Mikolajczyk, Matthijs Moed, Romana T Netea-Maier, Ilja M Nolte, Yukinori Okada, Mauro Pala, Cristian Pattaro, Oluf Pedersen, Astrid Petersmann, Eleonora Porcu, Iris Postmus, Peter P Pramstaller, Bruce M Psaty, Yolande F M Ramos, Rajesh Rawal, Paul Redmond, J Brent Richards, Ernst R Rietzschel, Fernando Rivadeneira, Greet Roef, Jerome I Rotter, Cinzia F Sala, David Schlessinger, Elizabeth Selvin, P Eline Slagboom, Nicole Soranzo, Thorkild I A Sørensen, Timothy D Spector, John M Starr, David J Stott, Youri Taes, Daniel Taliun, Toshiko Tanaka, Betina Thuesen, Daniel Tiller, Daniela Toniolo, Andre G Uitterlinden, W Edward Visser, John P Walsh, Scott G Wilson, Bruce H R Wolffenbuttel, Qiong Yang, Hou-Feng Zheng, Anne Cappola, Robin P Peeters, Silvia Naitza, Henry Völzke, Serena Sanna, Anna Köttgen, Theo J Visser, Marco Medici, Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation., Nature communications, 10.1038/s41467-018-06356-1, 9, 1, 4455-4455, 2018.10, Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets..
20. Masahiro Kanai, Masato Akiyama, Atsushi Takahashi, Nana Matoba, Yukihide Momozawa, Masashi Ikeda, Nakao Iwata, Shiro Ikegawa, Makoto Hirata, Koichi Matsuda, Michiaki Kubo, Yukinori Okada, Yoichiro Kamatani, Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases., Nature genetics, 10.1038/s41588-018-0047-6, 50, 3, 390-400, 2018.03, Clinical measurements can be viewed as useful intermediate phenotypes to promote understanding of complex human diseases. To acquire comprehensive insights into the underlying genetics, here we conducted a genome-wide association study (GWAS) of 58 quantitative traits in 162,255 Japanese individuals. Overall, we identified 1,407 trait-associated loci (P < 5.0 × 10-8), 679 of which were novel. By incorporating 32 additional GWAS results for complex diseases and traits in Japanese individuals, we further highlighted pleiotropy, genetic correlations, and cell-type specificity across quantitative traits and diseases, which substantially expands the current understanding of the associated genetics and biology. This study identified both shared polygenic effects and cell-type specificity, represented by the genetic links among clinical measurements, complex diseases, and relevant cell types. Our findings demonstrate that even without prior biological knowledge of cross-phenotype relationships, genetics corresponding to clinical measurements successfully recapture those measurements' relevance to diseases, and thus can contribute to the elucidation of unknown etiology and pathogenesis..
21. Momoko Horikoshi, Felix R Day, Masato Akiyama, Makoto Hirata, Yoichiro Kamatani, Koichi Matsuda, Kazuyoshi Ishigaki, Masahiro Kanai, Hollis Wright, Carlos A Toro, Sergio R Ojeda, Alejandro Lomniczi, Michiaki Kubo, Ken K Ong, John R B Perry, Elucidating the genetic architecture of reproductive ageing in the Japanese population., Nature communications, 10.1038/s41467-018-04398-z, 9, 1, 1977-1977, 2018.05, Population studies elucidating the genetic architecture of reproductive ageing have been largely limited to European ancestries, restricting the generalizability of the findings and overlooking possible key genes poorly captured by common European genetic variation. Here, we report 26 loci (all P < 5 × 10-8) for reproductive ageing, i.e. puberty timing or age at menopause, in a non-European population (up to 67,029 women of Japanese ancestry). Highlighted genes for menopause include GNRH1, which supports a primary, rather than passive, role for hypothalamic-pituitary GnRH signalling in the timing of menopause. For puberty timing, we demonstrate an aetiological role for receptor-like protein tyrosine phosphatases by combining evidence across population genetics and pre- and peri-pubertal changes in hypothalamic gene expression in rodent and primate models. Furthermore, our findings demonstrate widespread differences in allele frequencies and effect estimates between Japanese and European associated variants, highlighting the benefits and challenges of large-scale trans-ethnic approaches..
22. Yukinori Okada, Yukihide Momozawa, Saori Sakaue, Masahiro Kanai, Kazuyoshi Ishigaki, Masato Akiyama, Toshihiro Kishikawa, Yasumichi Arai, Takashi Sasaki, Kenjiro Kosaki, Makoto Suematsu, Koichi Matsuda, Kazuhiko Yamamoto, Michiaki Kubo, Nobuyoshi Hirose, Yoichiro Kamatani, Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese., Nature communications, 10.1038/s41467-018-03274-0, 9, 1, 1631-1631, 2018.04, Understanding natural selection is crucial to unveiling evolution of modern humans. Here, we report natural selection signatures in the Japanese population using 2234 high-depth whole-genome sequence (WGS) data (25.9×). Using rare singletons, we identify signals of very recent selection for the past 2000-3000 years in multiple loci (ADH cluster, MHC region, BRAP-ALDH2, SERHL2). In large-scale genome-wide association study (GWAS) dataset (n = 171,176), variants with selection signatures show enrichment in heterogeneity of derived allele frequency spectra among the geographic regions of Japan, highlighted by two major regional clusters (Hondo and Ryukyu). While the selection signatures do not show enrichment in archaic hominin-derived genome sequences, they overlap with the SNPs associated with the modern human traits. The strongest overlaps are observed for the alcohol or nutrition metabolism-related traits. Our study illustrates the value of high-depth WGS to understand evolution and their relationship with disease risk..
23. Buhm Han, Masato Akiyama, Kyung-Kon Kim, Hyunjung Oh, Hyunchul Choi, Cue Hyunkyu Lee, Seulgi Jung, Ho-Su Lee, Emma E Kim, Seungho Cook, Talin Haritunians, Keiko Yamazaki, Sang Hyoung Park, Byong Duk Ye, Dermot P B McGovern, Motohiro Esaki, Takaaki Kawaguchi, Seik-Soon Khor, Kent D Taylor, Jerome I Rotter, Yasuo Suzuki, Toshiyuki Matsui, Satoshi Motoya, So-Young Bang, Tae-Hwan Kim, Yukihide Momozawa, Yoichiro Kamatani, Katsushi Tokunaga, Michiaki Kubo, Yukinori Okada, Suk-Kyun Yang, Kyuyoung Song, Amino acid position 37 of HLA-DRβ1 affects susceptibility to Crohn's disease in Asians., Human molecular genetics, 10.1093/hmg/ddy285, 27, 22, 3901-3910, 2018.11, Crohn's disease (CD) and ulcerative colitis (UC) are the major types of chronic inflammatory bowel disease (IBD) characterized by recurring episodes of inflammation of the gastrointestinal tract. Although it is well established that human leukocyte antigen (HLA) is a major risk factor for IBD, it is yet to be determined which HLA alleles or amino acids drive the risks of CD and UC in Asians. To define the roles of HLA for IBD in Asians, we fine-mapped HLA in 12 568 individuals from Korea and Japan (3294 patients with CD, 1522 patients with UC and 7752 controls). We identified that the amino acid position 37 of HLA-DRβ1 plays a key role in the susceptibility to CD (presence of serine being protective, P = 3.6 × 10-67, OR = 0.48 [0.45-0.52]). For UC, we confirmed the known association of the haplotype spanning HLA-C*12:02, HLA-B*52:01 and HLA-DRB1*1502 (P = 1.2 × 10-28, OR = 4.01 [3.14-5.12])..
24. Adrienne Tin, Jonathan Marten, Victoria L Halperin Kuhns, Yong Li, Matthias Wuttke, Holger Kirsten, Karsten B Sieber, Chengxiang Qiu, Mathias Gorski, Zhi Yu, Ayush Giri, Gardar Sveinbjornsson, Man Li, Audrey Y Chu, Anselm Hoppmann, Luke J O'Connor, Bram Prins, Teresa Nutile, Damia Noce, Masato Akiyama, Massimiliano Cocca, Sahar Ghasemi, Peter J van der Most, Katrin Horn, Yizhe Xu, Christian Fuchsberger, Sanaz Sedaghat, Saima Afaq, Najaf Amin, Johan Ärnlöv, Stephan J L Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L Biggs, Ginevra Biino, Eric Boerwinkle, Erwin P Bottinger, Thibaud S Boutin, Marco Brumat, Ralph Burkhardt, Eric Campana, Archie Campbell, Harry Campbell, Robert J Carroll, Eulalia Catamo, John C Chambers, Marina Ciullo, Maria Pina Concas, Josef Coresh, Tanguy Corre, Daniele Cusi, Sala Cinzia Felicita, Martin H de Borst, Alessandro De Grandi, Renée de Mutsert, Aiko P J de Vries, Graciela Delgado, Ayşe Demirkan, Olivier Devuyst, Katalin Dittrich, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Michele K Evans, Ron T Gansevoort, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Martin Gögele, Scott D Gordon, Daniel F Gudbjartsson, Vilmundur Gudnason, Toomas Haller, Pavel Hamet, Tamara B Harris, Caroline Hayward, Andrew A Hicks, Edith Hofer, Hilma Holm, Wei Huang, Nina Hutri-Kähönen, Shih-Jen Hwang, M Arfan Ikram, Raychel M Lewis, Erik Ingelsson, Johanna Jakobsdottir, Ingileif Jonsdottir, Helgi Jonsson, Peter K Joshi, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Yoichiro Kamatani, Masahiro Kanai, Shona M Kerr, Wieland Kiess, Marcus E Kleber, Wolfgang Koenig, Jaspal S Kooner, Antje Körner, Peter Kovacs, Bernhard K Krämer, Florian Kronenberg, Michiaki Kubo, Brigitte Kühnel, Martina La Bianca, Leslie A Lange, Benjamin Lehne, Terho Lehtimäki, Jun Liu, Markus Loeffler, Ruth J F Loos, Leo-Pekka Lyytikäinen, Reedik Magi, Anubha Mahajan, Nicholas G Martin, Winfried März, Deborah Mascalzoni, Koichi Matsuda, Christa Meisinger, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Christopher J O'Donnell, Otis D Wilson, J Michael Gaziano, Pashupati P Mishra, Karen L Mohlke, Nina Mononen, Grant W Montgomery, Dennis O Mook-Kanamori, Martina Müller-Nurasyid, Girish N Nadkarni, Mike A Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M Nolte, Raymond Noordam, Jeffrey R O'Connell, Isleifur Olafsson, Sandosh Padmanabhan, Brenda W J H Penninx, Thomas Perls, Annette Peters, Mario Pirastu, Nicola Pirastu, Giorgio Pistis, Ozren Polasek, Belen Ponte, David J Porteous, Tanja Poulain, Michael H Preuss, Ton J Rabelink, Laura M Raffield, Olli T Raitakari, Rainer Rettig, Myriam Rheinberger, Kenneth M Rice, Federica Rizzi, Antonietta Robino, Igor Rudan, Alena Krajcoviechova, Renata Cifkova, Rico Rueedi, Daniela Ruggiero, Kathleen A Ryan, Yasaman Saba, Erika Salvi, Helena Schmidt, Reinhold Schmidt, Christian M Shaffer, Albert V Smith, Blair H Smith, Cassandra N Spracklen, Konstantin Strauch, Michael Stumvoll, Patrick Sulem, Salman M Tajuddin, Andrej Teren, Joachim Thiery, Chris H L Thio, Unnur Thorsteinsdottir, Daniela Toniolo, Anke Tönjes, Johanne Tremblay, André G Uitterlinden, Simona Vaccargiu, Pim van der Harst, Cornelia M van Duijn, Niek Verweij, Uwe Völker, Peter Vollenweider, Gerard Waeber, Melanie Waldenberger, John B Whitfield, Sarah H Wild, James F Wilson, Qiong Yang, Weihua Zhang, Alan B Zonderman, Murielle Bochud, James G Wilson, Sarah A Pendergrass, Kevin Ho, Afshin Parsa, Peter P Pramstaller, Bruce M Psaty, Carsten A Böger, Harold Snieder, Adam S Butterworth, Yukinori Okada, Todd L Edwards, Kari Stefansson, Katalin Susztak, Markus Scholz, Iris M Heid, Adriana M Hung, Alexander Teumer, Cristian Pattaro, Owen M Woodward, Veronique Vitart, Anna Köttgen, Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels., Nature genetics, 10.1038/s41588-019-0504-x, 51, 10, 1459-1474, 2019.10, Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits..
25. Masataka Ishizu, Yusuke Murakami, Kohta Fujiwara, Jun Funatsu, Shotaro Shimokawa, Shunji Nakatake, Takashi Tachibana, Toshio Hisatomi, Yoshito Koyanagi, Masato Akiyama, Yukihide Momozawa, Tatsuro Ishibashi, Koh-Hei Sonoda, Yasuhiro Ikeda, Relationships Between Serum Antioxidant and Oxidant Statuses and Visual Function in Retinitis Pigmentosa., Investigative ophthalmology & visual science, 10.1167/iovs.19-26927, 60, 13, 4462-4468, 2019.10, Purpose: To investigate the serum changes of antioxidant/oxidant markers and the relationship between these factors and visual function in patients with retinitis pigmentosa (RP). Methods: Fifty-two RP patients <40 years old and 25 controls were included. Serum samples were analyzed for superoxide dismutase 3 (SOD3) activity, glutathione peroxidase (GPx), potential antioxidant (PAO), and hexanoyl-lysine (HEL). The relationships between these markers and visual parameters, including best-corrected visual acuity (BCVA), mean deviation (MD), and average retinal sensitivity of 4 or 12 central points on static perimetry tests (Humphrey Field Analyzer, the central 10-2 program) were examined in the RP patients. Results: Although there was no significant difference in the serum SOD3 activity between RP patients and controls, serum SOD3 activity in the severe degeneration group with macular involvement (16.3 ± 11.3 U/mL) was significantly lower compared with those in the mild degeneration group (those with midperipheral scotomas; 28.5 ± 16.6 U/mL, P = 0.0459). SOD3 was significantly related to visual acuity (r = -0.3701, P = 0.0069) and the average retinal sensitivity of four central points (r = 0.3463, P = 0.0137) in RP patients. The linear trends of these two parameters across SOD3 levels were also significant (P = 0.0264 and 0.0172, respectively). There was no consistent correlation between other serum antioxidant/oxidant markers and visual parameters. Conclusions: Lower serum SOD3 activity was associated with the severe retinal degeneration in RP patients. Our results suggest that serum SOD3 activity may be related to disease severity in RP..
26. Koji M Nishiguchi, Yasuhiro Ikeda, Kosuke Fujita, Hiroshi Kunikata, Makoto Akiho, Kazuki Hashimoto, Katsuhiro Hosono, Kentaro Kurata, Yoshito Koyanagi, Masato Akiyama, Takefumi Suzuki, Ryo Kawasaki, Yuko Wada, Yoshihiro Hotta, Koh-Hei Sonoda, Akira Murakami, Mitsuru Nakazawa, Toru Nakazawa, Toshiaki Abe, Phenotypic Features of Oguchi Disease and Retinitis Pigmentosa in Patients with S-Antigen Mutations: A Long-Term Follow-up Study., Ophthalmology, 10.1016/j.ophtha.2019.05.027, 126, 11, 1557-1566, 2019.11, PURPOSE: To present phenotypic features of 22 patients with S-antigen (SAG) mutations. DESIGN: Retrospective cohort study. PARTICIPANTS: Twenty-one Japanese patients from 16 families with a homozygous c.924delA mutation and 1 patient with a homozygous c.636delT mutation in the SAG gene. METHODS: Clinical records on symptoms; best-corrected visual acuity; and Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), OCT, and electroretinography results were reviewed. MAIN OUTCOME MEASURES: Best-corrected visual acuity, Goldmann perimetry results, imaging findings, and electroretinography results. RESULTS: Ten patients had Oguchi disease and 12 had retinitis pigmentosa (RP) with mean follow-up periods of 13.8 and 10.2 years, respectively. Retinitis pigmentosa patients were older (mean age, 56.0 years) than those with Oguchi disease (mean age, 22.1 years; P < 0.001) at the initial visit. Night blindness noted in childhood was the most common initial symptom for both Oguchi disease (80.0%) and RP (91.7%) patients. Best-corrected visual acuity in the logarithm of the minimum angle of resolution (logMAR) was well preserved in Oguchi disease patients (mean, 0.02 logMAR in both eyes) but reduced in most RP patients (mean, 1.32 logMAR [right eye] and 1.35 logMAR [left eye]). Similarly, the visual field in the retinal area was preserved in Oguchi disease patients (mean, 677 mm2 right eye and 667 mm2 left eye) and reduced in RP patients (mean, 369 mm2 right eye and 294 mm2 left eye). Fundus images revealed a characteristic golden sheen with no retinal degeneration in Oguchi disease patients, excluding 2 with macular degeneration detected by FAF, OCT, or both and 1 with mild retinal degeneration confirmed by OCT and fluorescein angiography. Pigmentary retinal degeneration most evident posteriorly was observed in RP patients, accompanied by a characteristic golden sheen in 12 of 14 patients undergoing ultra-widefield fundus imaging. OCT showed disrupted macular structure, and FAF revealed variable hypofluorescence. Electroretinography identified absent rod responses in both diseases, along with relative preservation of cone responses in Oguchi disease patients. Three patients showed progressive loss of the golden sheen based on fundus images, including 1 who demonstrated RP 26 years after the initial diagnosis of Oguchi disease. CONCLUSIONS: Retinitis pigmentosa with SAG mutations often shows a characteristic golden sheen surrounding posterior pigmentary retinal degeneration. Oguchi disease can show progressive degeneration in adulthood, rarely resulting in RP..
27. Ken Suzuki, Masato Akiyama, Kazuyoshi Ishigaki, Masahiro Kanai, Jun Hosoe, Nobuhiro Shojima, Atsushi Hozawa, Aya Kadota, Kiyonori Kuriki, Mariko Naito, Kozo Tanno, Yasushi Ishigaki, Makoto Hirata, Koichi Matsuda, Nakao Iwata, Masashi Ikeda, Norie Sawada, Taiki Yamaji, Motoki Iwasaki, Shiro Ikegawa, Shiro Maeda, Yoshinori Murakami, Kenji Wakai, Shoichiro Tsugane, Makoto Sasaki, Masayuki Yamamoto, Yukinori Okada, Michiaki Kubo, Yoichiro Kamatani, Momoko Horikoshi, Toshimasa Yamauchi, Takashi Kadowaki, Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population., Nature genetics, 10.1038/s41588-018-0332-4, 51, 3, 379-386, 2019.03, To understand the genetics of type 2 diabetes in people of Japanese ancestry, we conducted A meta-analysis of four genome-wide association studies (GWAS; 36,614 cases and 155,150 controls of Japanese ancestry). We identified 88 type 2 diabetes-associated loci (P < 5.0 × 10-8) with 115 independent signals (P < 5.0 × 10-6), of which 28 loci with 30 signals were novel. Twenty-eight missense variants were in linkage disequilibrium (r2 > 0.6) with the lead variants. Among the 28 missense variants, three previously unreported variants had distinct minor allele frequency (MAF) spectra between people of Japanese and European ancestry (MAFJPN > 0.05 versus MAFEUR < 0.01), including missense variants in genes related to pancreatic acinar cells (GP2) and insulin secretion (GLP1R). Transethnic comparisons of the molecular pathways identified from the GWAS results highlight both ethnically shared and heterogeneous effects of a series of pathways on type 2 diabetes (for example, monogenic diabetes and beta cells)..
28. Emiko Noguchi, Masato Akiyama, Akiko Yagami, Tomomitsu Hirota, Yukinori Okada, Zenichiro Kato, Reiko Kishikawa, Yuma Fukutomi, Michihiro Hide, Eishin Morita, Michiko Aihara, Makiko Hiragun, Yuko Chinuki, Takahiro Okabe, Akiko Ito, Atsuko Adachi, Atsushi Fukunaga, Yumiko Kubota, Toshiyuki Aoki, Youko Aoki, Kazue Nishioka, Tetsuya Adachi, Nobuo Kanazawa, Hitoshi Miyazawa, Hiroyuki Sakai, Takehito Kozuka, Hideo Kitamura, Hideo Hashizume, Chiharu Kanegane, Koji Masuda, Kumiya Sugiyama, Reiko Tokuda, Junichi Furuta, Ikkou Higashimoto, Atsuko Kato, Mariko Seishima, Akihiko Tajiri, Atsuko Tomura, Hiroko Taniguchi, Hiroto Kojima, Hidenori Tanaka, Aiko Sakai, Wataru Morii, Masashi Nakamura, Yoichiro Kamatani, Atsushi Takahashi, Michiaki Kubo, Mayumi Tamari, Hirohisa Saito, Kayoko Matsunaga, HLA-DQ and RBFOX1 as susceptibility genes for an outbreak of hydrolyzed wheat allergy., The Journal of allergy and clinical immunology, 10.1016/j.jaci.2019.06.034, 144, 5, 1354-1363, 2019.11, BACKGROUND: Food allergy is a growing health problem worldwide because of its increasing prevalence, life-threatening potential, and shortage of effective preventive treatments. In an outbreak of wheat allergy in Japan, thousands of patients had allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP). OBJECTIVES: The aim of the present study was to investigate genetic variation that can contribute to susceptibility to HWP allergy. METHODS: We conducted a genome-wide association study of HWP allergy in 452 cases and 2700 control subjects using 6.6 million genotyped or imputed single nucleotide polymorphisms. Replication was assessed by genotyping single nucleotide polymorphisms in independent samples comprising 45 patients with HWP allergy and 326 control subjects. RESULTS: Through the genome-wide association study, we identified significant associations with the class II HLA region on 6p21 (P = 2.16 × 10-24 for rs9271588 and P = 2.96 × 10-24 for HLA-DQα1 amino acid position 34) and with the RBFOX1 locus at 16p13 (rs74575857, P = 8.4 × 10-9). The associations were also confirmed in the replication data set. Both amino acid polymorphisms (HLA-DQβ1 amino acid positions 13 and 26) located in the P4 binding pockets on the HLA-DQ molecule achieved the genome-wide significance level (P < 5.0 × 10-8). CONCLUSIONS: Our data provide the first demonstration of genetic risk for HWP allergy and show that this genetic risk is mainly represented by multiple combinations of HLA variants..
29. Ikuo Otsuka, Masato Akiyama, Osamu Shirakawa, Satoshi Okazaki, Yukihide Momozawa, Yoichiro Kamatani, Takeshi Izumi, Shusuke Numata, Motonori Takahashi, Shuken Boku, Ichiro Sora, Ken Yamamoto, Yasuhiro Ueno, Tatsushi Toda, Michiaki Kubo, Akitoyo Hishimoto, Genome-wide association studies identify polygenic effects for completed suicide in the Japanese population., Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 10.1038/s41386-019-0506-5, 44, 12, 2119-2124, 2019.11, Suicide is a significant public health problem worldwide, and several Asian countries including Japan have relatively high suicide rates on a world scale. Twin, family, and adoption studies have suggested high heritability for suicide, but genetics lags behind due to difficulty in obtaining samples from individuals who died by suicide, especially in non-European populations. In this study, we carried out genome-wide association studies combining two independent datasets totaling 746 suicides and 14,049 non-suicide controls in the Japanese population. Although we identified no genome-wide significant single-nucleotide polymorphisms (SNPs), we demonstrated significant SNP-based heritability (35-48%; P < 0.001) for completed suicide by genomic restricted maximum-likelihood analysis and a shared genetic risk between two datasets (Pbest = 2.7 × 10-13) by polygenic risk score analysis. This study is the first genome-wide association study for suicidal behavior in an East Asian population, and our results provided the evidence of polygenic architecture underlying completed suicide..
30. Yoshito Koyanagi, Masato Akiyama, Koji M Nishiguchi, Yukihide Momozawa, Yoichiro Kamatani, Sadaaki Takata, Chihiro Inai, Yusuke Iwasaki, Mikako Kumano, Yusuke Murakami, Kazuko Omodaka, Toshiaki Abe, Shiori Komori, Dan Gao, Toshiaki Hirakata, Kentaro Kurata, Katsuhiro Hosono, Shinji Ueno, Yoshihiro Hotta, Akira Murakami, Hiroko Terasaki, Yuko Wada, Toru Nakazawa, Tatsuro Ishibashi, Yasuhiro Ikeda, Michiaki Kubo, Koh-Hei Sonoda, Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients., Journal of medical genetics, 10.1136/jmedgenet-2018-105691, 56, 10, 662-670, 2019.10, BACKGROUND: The genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population. METHODS: A total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases. RESULTS: We successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658*) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases. CONCLUSIONS: East Asian-specific variants in causative genes were the major causes of RP in the Japanese population..
31. Jun Hirata, Kazuyoshi Hosomichi, Saori Sakaue, Masahiro Kanai, Hirofumi Nakaoka, Kazuyoshi Ishigaki, Ken Suzuki, Masato Akiyama, Toshihiro Kishikawa, Kotaro Ogawa, Tatsuo Masuda, Kenichi Yamamoto, Makoto Hirata, Koichi Matsuda, Yukihide Momozawa, Ituro Inoue, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Genetic and phenotypic landscape of the major histocompatibilty complex region in the Japanese population., Nature genetics, 10.1038/s41588-018-0336-0, 51, 3, 470-480, 2019.03, To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data (n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals. A phenome-wide association study assessing 106 clinical phenotypes identified abundant, significant genotype-phenotype associations across 52 phenotypes. Fine-mapping highlighted multiple association patterns conferring independent risks from classical HLA genes. Region-wide heritability estimates and genetic-correlation network analysis elucidated the polygenic architecture shared across the phenotypes..
32. Nana Matoba, Masato Akiyama, Kazuyoshi Ishigaki, Masahiro Kanai, Atsushi Takahashi, Yukihide Momozawa, Shiro Ikegawa, Masashi Ikeda, Nakao Iwata, Makoto Hirata, Koichi Matsuda, Michiaki Kubo, Yukinori Okada, Yoichiro Kamatani, GWAS of smoking behaviour in 165,436 Japanese people reveals seven new loci and shared genetic architecture., Nature human behaviour, 10.1038/s41562-019-0557-y, 3, 5, 471-477, 2019.05, Cigarette smoking is a risk factor for a wide range of human diseases1. To investigate the genetic components associated with smoking behaviours in the Japanese population, we conducted a genome-wide association study of four smoking-related traits using up to 165,436 individuals. In total, we identified seven new loci, including three loci associated with the number of cigarettes per day (EPHX2-CLU, RET and CUX2-ALDH2), three loci associated with smoking initiation (DLC1, CXCL12-TMEM72-AS1 and GALR1-SALL3) and LINC01793-MIR4432HG, associated with the age of smoking initiation. Of these, three loci (LINC01793-MIR4432HG, CXCL12-TMEM72-AS1 and GALR1-SALL3) were found by conducting an additional sex-stratified genome-wide association study. This additional analysis showed heterogeneity of effects between sexes. The cross-sex linkage disequilibrium score regression2,3 analysis also indicated that the genetic component of smoking initiation was significantly different between the sexes. Cross-trait linkage disequilibrium score regression analysis and trait-relevant tissue analysis showed that the number of cigarettes per day has a specific genetic background distinct from those of the other three smoking behaviours. We also report 11 diseases that share genetic basis with smoking behaviours. Although the current study should be carefully considered owing to the lack of replication samples, our findings characterized the genetic architecture of smoking behaviours. Further studies in East Asian populations are warranted to confirm our findings..
33. Chikashi Terao, Yukihide Momozawa, Kazuyoshi Ishigaki, Eiryo Kawakami, Masato Akiyama, Po-Ru Loh, Giulio Genovese, Hiroki Sugishita, Tazro Ohta, Makoto Hirata, John R B Perry, Koichi Matsuda, Yoshinori Murakami, Michiaki Kubo, Yoichiro Kamatani, GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation., Nature communications, 10.1038/s41467-019-12705-5, 10, 1, 4719-4719, 2019.10, Mosaic loss of chromosome Y (mLOY) is frequently observed in the leukocytes of ageing men. However, the genetic architecture and biological mechanisms underlying mLOY are not fully understood. In a cohort of 95,380 Japanese men, we identify 50 independent genetic markers in 46 loci associated with mLOY at a genome-wide significant level, 35 of which are unreported. Lead markers overlap enhancer marks in hematopoietic stem cells (HSCs, P ≤ 1.0 × 10-6). mLOY genome-wide association study signals exhibit polygenic architecture and demonstrate strong heritability enrichment in regions surrounding genes specifically expressed in multipotent progenitor (MPP) cells and HSCs (P ≤ 3.5 × 10-6). ChIP-seq data demonstrate that binding sites of FLI1, a fate-determining factor promoting HSC differentiation into platelets rather than red blood cells (RBCs), show a strong heritability enrichment (P = 1.5 × 10-6). Consistent with these findings, platelet and RBC counts are positively and negatively associated with mLOY, respectively. Collectively, our observations improve our understanding of the mechanisms underlying mLOY..
34. Shunji Nakatake, Yusuke Murakami, Jun Funatsu, Yoshito Koyanagi, Masato Akiyama, Yukihide Momozawa, Tatsuro Ishibashi, Koh-Hei Sonoda, Yasuhiro Ikeda, Early detection of cone photoreceptor cell loss in retinitis pigmentosa using adaptive optics scanning laser ophthalmoscopy., Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 10.1007/s00417-019-04307-0, 257, 6, 1169-1181, 2019.06, PURPOSE: The purpose of the study was to investigate the characteristics of the parafoveal cone density changes in patients with retinitis pigmentosa (RP) using adaptive optics scanning laser ophthalmoscopy (AO-SLO). METHODS: A total of 14 eyes of RP patients and 10 eyes of control subjects were examined. High-resolution images of cone photoreceptor cells were obtained with a Canon AO-SLO system in the four retinal regions of the superior, inferior, temporal, and nasal areas located 1.0 mm from the central fovea. The relationships of cone density with optical coherence tomography (OCT) findings and the visual sensitivity of the static perimetry tests were analyzed in RP patients. RESULTS: The averaged cone densities in RP patients were decreased at 1.0 mm eccentricity from the fovea (11,899 cells/mm2) compared with those in control subjects (16,647 cells/mm2; P < 0.01). The cone density was substantially decreased even in RP patients with an intact interdigitation zone at the examined area (12,865 cells/mm2; P < 0.01 vs. controls) and preserved visual sensitivity with > 35 dB (13,019 cells/mm2; P < 0.001 vs. controls). CONCLUSIONS: In RP, cone photoreceptor cell loss occurred in the parafoveal region with a preserved EZ/IZ or visual sensitivity. AO-SLO may be a useful modality to detect early changes of cone photoreceptor cells in RP patients..
35. Masato Akiyama, Kazuyoshi Ishigaki, Saori Sakaue, Yukihide Momozawa, Momoko Horikoshi, Makoto Hirata, Koichi Matsuda, Shiro Ikegawa, Atsushi Takahashi, Masahiro Kanai, Sadao Suzuki, Daisuke Matsui, Mariko Naito, Taiki Yamaji, Motoki Iwasaki, Norie Sawada, Kozo Tanno, Makoto Sasaki, Atsushi Hozawa, Naoko Minegishi, Kenji Wakai, Shoichiro Tsugane, Atsushi Shimizu, Masayuki Yamamoto, Yukinori Okada, Yoshinori Murakami, Michiaki Kubo, Yoichiro Kamatani, Characterizing rare and low-frequency height-associated variants in the Japanese population., Nature communications, 10.1038/s41467-019-12276-5, 10, 1, 4393-4393, 2019.09, Human height is a representative phenotype to elucidate genetic architecture. However, the majority of large studies have been performed in European population. To investigate the rare and low-frequency variants associated with height, we construct a reference panel (N = 3,541) for genotype imputation by integrating the whole-genome sequence data from 1,037 Japanese with that of the 1000 Genomes Project, and perform a genome-wide association study in 191,787 Japanese. We report 573 height-associated variants, including 22 rare and 42 low-frequency variants. These 64 variants explain 1.7% of the phenotypic variance. Furthermore, a gene-based analysis identifies two genes with multiple height-increasing rare and low-frequency nonsynonymous variants (SLC27A3 and CYP26B1; PSKAT-O < 2.5 × 10-6). Our analysis shows a general tendency of the effect sizes of rare variants towards increasing height, which is contrary to findings among Europeans, suggesting that height-associated rare variants are under different selection pressure in Japanese and European populations..
36. David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian'an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai Carmi, Mark J Caulfield, David Cesarini, John C Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J Deary, Rajkumar Dorajoo, Cornelia M van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G Eriksson, Evangelos Evangelou, Michele K Evans, Jessica D Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F A Grant, Lyn R Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A Hicks, Hagit Hochner, Heikki Huikuri, Steven C Hunt, Vincent W V Jaddoe, Philip L De Jager, Magnus Johannesson, Åsa Johansson, Jost B Jonas, J Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L R Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W van der Laan, Jari Lahti, Matthias Laudes, Rodney A Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G Martin, Winfried März, Giuseppe Matullo, Mark I McCarthy, Sarah E Medland, Tony R Merriman, Andres Metspalu, Brian F Meyer, Karen L Mohlke, Grant W Montgomery, Dennis Mook-Kanamori, Patricia B Munroe, Kari E North, Dale R Nyholt, Jeffery R O'connell, Carole Ober, Albertine J Oldehinkel, Walter Palmas, Colin Palmer, Gerard G Pasterkamp, Etienne Patin, Craig E Pennell, Louis Perusse, Patricia A Peyser, Mario Pirastu, Tinca J C Polderman, David J Porteous, Danielle Posthuma, Bruce M Psaty, John D Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I Rotter, Igor Rudan, Hester M Den Ruijter, Dharambir K Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Robert A Scott, Alan R Shuldiner, Xueling Sim, Neil Small, Jennifer A Smith, Nona Sotoodehnia, E-Shyong Tai, Alexander Teumer, Nicholas J Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A Wang, David R Weir, John B Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S Zemel, Alan B Zonderman, Markus Perola, Patrik K E Magnusson, André G Uitterlinden, Jaspal S Kooner, Daniel I Chasman, Ruth J F Loos, Nora Franceschini, Lude Franke, Chris S Haley, Caroline Hayward, Robin G Walters, John R B Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K Joshi, Michiaki Kubo, James F Wilson, Associations of autozygosity with a broad range of human phenotypes., Nature communications, 10.1038/s41467-019-12283-6, 10, 1, 4957-4957, 2019.10, In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding..
37. Tao Huang, Tiange Wang, Yan Zheng, Christina Ellervik, Xiang Li, Meng Gao, Zhe Fang, Jin-Fang Chai, Tarun Veer S Ahluwalia, Yujie Wang, Trudy Voortman, Raymond Noordam, Alexis Frazier-Wood, Markus Scholz, Emily Sonestedt, Masato Akiyama, Rajkumar Dorajoo, Ang Zhou, Tuomas O Kilpeläinen, Marcus E Kleber, Sarah R Crozier, Keith M Godfrey, Rozenn Lemaitre, Janine F Felix, Yuan Shi, Preeti Gupta, Chiea-Chuen Khor, Terho Lehtimäki, Carol A Wang, Carla M T Tiesler, Elisabeth Thiering, Marie Standl, Peter Rzehak, Eirini Marouli, Meian He, Cécile Lecoeur, Dolores Corella, Chao-Qiang Lai, Luis A Moreno, Niina Pitkänen, Colin A Boreham, Tao Zhang, Seang Mei Saw, Paul M Ridker, Mariaelisa Graff, Frank J A van Rooij, Andre G Uitterlinden, Albert Hofman, Diana van Heemst, Frits R Rosendaal, Renée de Mutsert, Ralph Burkhardt, Christina-Alexandra Schulz, Ulrika Ericson, Yoichiro Kamatani, Jian-Min Yuan, Chris Power, Torben Hansen, Thorkild I A Sørensen, Anne Tjønneland, Kim Overvad, Graciela Delgado, Cyrus Cooper, Luc Djousse, Fernando Rivadeneira, Karen Jameson, Wanting Zhao, Jianjun Liu, Nanette R Lee, Olli Raitakari, Mika Kähönen, Jorma Viikari, Veit Grote, Jean-Paul Langhendries, Berthold Koletzko, Joaquin Escribano, Elvira Verduci, George Dedoussis, Caizheng Yu, Yih Chung Tham, Blanche Lim, Sing Hui Lim, Philippe Froguel, Beverley Balkau, Nadia R Fink, Rebecca K Vinding, Astrid Sevelsted, Hans Bisgaard, Oscar Coltell, Jean Dallongeville, Frédéric Gottrand, Katja Pahkala, Harri Niinikoski, Elina Hyppönen, Oluf Pedersen, Winfried März, Hazel Inskip, Vincent W V Jaddoe, Elaine Dennison, Tien Yin Wong, Charumathi Sabanayagam, E-Shyong Tai, Karen L Mohlke, David A Mackey, Dariusz Gruszfeld, Panagiotis Deloukas, Katherine L Tucker, Frédéric Fumeron, Klaus Bønnelykke, Peter Rossing, Ramon Estruch, Jose M Ordovas, Donna K Arnett, Aline Meirhaeghe, Philippe Amouyel, Ching-Yu Cheng, Xueling Sim, Yik Ying Teo, Rob M van Dam, Woon-Puay Koh, Marju Orho-Melander, Markus Loeffler, Michiaki Kubo, Joachim Thiery, Dennis O Mook-Kanamori, Dariush Mozaffarian, Bruce M Psaty, Oscar H Franco, Tangchun Wu, Kari E North, George Davey Smith, Jorge E Chavarro, Daniel I Chasman, Lu Qi, Association of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study., JAMA network open, 10.1001/jamanetworkopen.2019.10915, 2, 9, e1910915, 2019.09, Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures: Type 2 diabetes and glycemic traits. Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (β = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms..
38. Jun Inaishi, Yoichiro Hirakawa, Momoko Horikoshi, Masato Akiyama, Mayu Higashioka, Masahito Yoshinari, Jun Hata, Naoko Mukai, Yoichiro Kamatani, Yukihide Momozawa, Michiaki Kubo, Toshiharu Ninomiya, Association Between Genetic Risk and Development of Type 2 Diabetes in a General Japanese Population: The Hisayama Study., The Journal of clinical endocrinology and metabolism, 10.1210/jc.2018-01782, 104, 8, 3213-3222, 2019.08, CONTEXT: Although recent genetic studies have identified many susceptibility loci associated with type 2 diabetes (T2D), the usefulness of such loci for precision medicine remains uncertain. OBJECTIVE: This study investigated the impact of genetic risk score (GRS) on the development of T2D in a general Japanese population. PARTICIPANTS: The current study consists of 1465 subjects aged 40 to 79 years without diabetes who underwent a health examination in 2002. DESIGN: The GRS was generated using the literature-based effect size for T2D of 84 susceptibility loci for the Japanese population, and the risk estimates of GRS on the incidence of T2D were computed by using a Cox proportional hazard model in a 10-year follow-up study. The influence of GRS on the predictive ability was estimated with Harrell C statistics, integrated discrimination improvement (IDI), and continuous net reclassification improvement (cNRI). RESULTS: During the 10-year follow-up, 199 subjects experienced T2D. The risk of developing T2D increased significantly with elevating quintiles of GRS (multivariable-adjusted hazard ratio for the fifth vs first quintile, 2.85; 95% CI, 1.83 to 4.44). When incorporating GRS into the multivariable model comprising environmental risk factors, the Harrell C statistics (95% CI) increased from 0.681 (0.645 to 0.717) to 0.707 (0.672 to 0.742) and the predictive ability of T2D was significantly improved (IDI, 0.0376; 95% CI, 0.0284 to 0.0494; cNRI, 0.3565; 95% CI, 0.1278 to 0.5829). GRS was also associated with the risk of T2D independently of environmental risk factors. CONCLUSIONS: These findings suggest the usefulness of GRS for identifying a high-risk population together with environmental risk factors in the Japanese population..
39. Konstantinos Nikopoulos, Katarina Cisarova, Mathieu Quinodoz, Hanna Koskiniemi-Kuendig, Noriko Miyake, Pietro Farinelli, Atta Ur Rehman, Muhammad Imran Khan, Andrea Prunotto, Masato Akiyama, Yoichiro Kamatani, Chikashi Terao, Fuyuki Miya, Yasuhiro Ikeda, Shinji Ueno, Nobuo Fuse, Akira Murakami, Yuko Wada, Hiroko Terasaki, Koh-Hei Sonoda, Tatsuro Ishibashi, Michiaki Kubo, Frans P M Cremers, Zoltán Kutalik, Naomichi Matsumoto, Koji M Nishiguchi, Toru Nakazawa, Carlo Rivolta, A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy., Nature communications, 10.1038/s41467-019-10746-4, 10, 1, 2884-2884, 2019.06, Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance..
40. Matthias Wuttke, Yong Li, Man Li, Karsten B Sieber, Mary F Feitosa, Mathias Gorski, Adrienne Tin, Lihua Wang, Audrey Y Chu, Anselm Hoppmann, Holger Kirsten, Ayush Giri, Jin-Fang Chai, Gardar Sveinbjornsson, Bamidele O Tayo, Teresa Nutile, Christian Fuchsberger, Jonathan Marten, Massimiliano Cocca, Sahar Ghasemi, Yizhe Xu, Katrin Horn, Damia Noce, Peter J van der Most, Sanaz Sedaghat, Zhi Yu, Masato Akiyama, Saima Afaq, Tarunveer S Ahluwalia, Peter Almgren, Najaf Amin, Johan Ärnlöv, Stephan J L Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L Biggs, Ginevra Biino, Michael Boehnke, Eric Boerwinkle, Mathilde Boissel, Erwin P Bottinger, Thibaud S Boutin, Hermann Brenner, Marco Brumat, Ralph Burkhardt, Adam S Butterworth, Eric Campana, Archie Campbell, Harry Campbell, Mickaël Canouil, Robert J Carroll, Eulalia Catamo, John C Chambers, Miao-Ling Chee, Miao-Li Chee, Xu Chen, Ching-Yu Cheng, Yurong Cheng, Kaare Christensen, Renata Cifkova, Marina Ciullo, Maria Pina Concas, James P Cook, Josef Coresh, Tanguy Corre, Cinzia Felicita Sala, Daniele Cusi, John Danesh, E Warwick Daw, Martin H de Borst, Alessandro De Grandi, Renée de Mutsert, Aiko P J de Vries, Frauke Degenhardt, Graciela Delgado, Ayse Demirkan, Emanuele Di Angelantonio, Katalin Dittrich, Jasmin Divers, Rajkumar Dorajoo, Kai-Uwe Eckardt, Georg Ehret, Paul Elliott, Karlhans Endlich, Michele K Evans, Janine F Felix, Valencia Hui Xian Foo, Oscar H Franco, Andre Franke, Barry I Freedman, Sandra Freitag-Wolf, Yechiel Friedlander, Philippe Froguel, Ron T Gansevoort, He Gao, Paolo Gasparini, J Michael Gaziano, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Franco Giulianini, Martin Gögele, Scott D Gordon, Daniel F Gudbjartsson, Vilmundur Gudnason, Toomas Haller, Pavel Hamet, Tamara B Harris, Catharina A Hartman, Caroline Hayward, Jacklyn N Hellwege, Chew-Kiat Heng, Andrew A Hicks, Edith Hofer, Wei Huang, Nina Hutri-Kähönen, Shih-Jen Hwang, M Arfan Ikram, Olafur S Indridason, Erik Ingelsson, Marcus Ising, Vincent W V Jaddoe, Johanna Jakobsdottir, Jost B Jonas, Peter K Joshi, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Yoichiro Kamatani, Candace M Kammerer, Masahiro Kanai, Mika Kastarinen, Shona M Kerr, Chiea-Chuen Khor, Wieland Kiess, Marcus E Kleber, Wolfgang Koenig, Jaspal S Kooner, Antje Körner, Peter Kovacs, Aldi T Kraja, Alena Krajcoviechova, Holly Kramer, Bernhard K Krämer, Florian Kronenberg, Michiaki Kubo, Brigitte Kühnel, Mikko Kuokkanen, Johanna Kuusisto, Martina La Bianca, Markku Laakso, Leslie A Lange, Carl D Langefeld, Jeannette Jen-Mai Lee, Benjamin Lehne, Terho Lehtimäki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia M Lindgren, Jun Liu, Jianjun Liu, Markus Loeffler, Ruth J F Loos, Susanne Lucae, Mary Ann Lukas, Leo-Pekka Lyytikäinen, Reedik Mägi, Patrik K E Magnusson, Anubha Mahajan, Nicholas G Martin, Jade Martins, Winfried März, Deborah Mascalzoni, Koichi Matsuda, Christa Meisinger, Thomas Meitinger, Olle Melander, Andres Metspalu, Evgenia K Mikaelsdottir, Yuri Milaneschi, Kozeta Miliku, Pashupati P Mishra, Karen L Mohlke, Nina Mononen, Grant W Montgomery, Dennis O Mook-Kanamori, Josyf C Mychaleckyj, Girish N Nadkarni, Mike A Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M Nolte, Raymond Noordam, Jeffrey O'Connell, Michelle L O'Donoghue, Isleifur Olafsson, Albertine J Oldehinkel, Marju Orho-Melander, Willem H Ouwehand, Sandosh Padmanabhan, Nicholette D Palmer, Runolfur Palsson, Brenda W J H Penninx, Thomas Perls, Markus Perola, Mario Pirastu, Nicola Pirastu, Giorgio Pistis, Anna I Podgornaia, Ozren Polasek, Belen Ponte, David J Porteous, Tanja Poulain, Peter P Pramstaller, Michael H Preuss, Bram P Prins, Michael A Province, Ton J Rabelink, Laura M Raffield, Olli T Raitakari, Dermot F Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M Rice, Paul M Ridker, Fernando Rivadeneira, Federica Rizzi, David J Roberts, Antonietta Robino, Peter Rossing, Igor Rudan, Rico Rueedi, Daniela Ruggiero, Kathleen A Ryan, Yasaman Saba, Charumathi Sabanayagam, Veikko Salomaa, Erika Salvi, Kai-Uwe Saum, Helena Schmidt, Reinhold Schmidt, Ben Schöttker, Christina-Alexandra Schulz, Nicole Schupf, Christian M Shaffer, Yuan Shi, Albert V Smith, Blair H Smith, Nicole Soranzo, Cassandra N Spracklen, Konstantin Strauch, Heather M Stringham, Michael Stumvoll, Per O Svensson, Silke Szymczak, E-Shyong Tai, Salman M Tajuddin, Nicholas Y Q Tan, Kent D Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H L Thio, Hauke Thomsen, Gudmar Thorleifsson, Daniela Toniolo, Anke Tönjes, Johanne Tremblay, Ioanna Tzoulaki, André G Uitterlinden, Simona Vaccargiu, Rob M van Dam, Pim van der Harst, Cornelia M van Duijn, Digna R Velez Edward, Niek Verweij, Suzanne Vogelezang, Uwe Völker, Peter Vollenweider, Gerard Waeber, Melanie Waldenberger, Lars Wallentin, Ya Xing Wang, Chaolong Wang, Dawn M Waterworth, Wen Bin Wei, Harvey White, John B Whitfield, Sarah H Wild, James F Wilson, Mary K Wojczynski, Charlene Wong, Tien-Yin Wong, Liang Xu, Qiong Yang, Masayuki Yasuda, Laura M Yerges-Armstrong, Weihua Zhang, Alan B Zonderman, Jerome I Rotter, Murielle Bochud, Bruce M Psaty, Veronique Vitart, James G Wilson, Abbas Dehghan, Afshin Parsa, Daniel I Chasman, Kevin Ho, Andrew P Morris, Olivier Devuyst, Shreeram Akilesh, Sarah A Pendergrass, Xueling Sim, Carsten A Böger, Yukinori Okada, Todd L Edwards, Harold Snieder, Kari Stefansson, Adriana M Hung, Iris M Heid, Markus Scholz, Alexander Teumer, Anna Köttgen, Cristian Pattaro, A catalog of genetic loci associated with kidney function from analyses of a million individuals., Nature genetics, 10.1038/s41588-019-0407-x, 51, 6, 957-972, 2019.06, Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research..
41. Hiroshi Matsunaga, Kaoru Ito, Masato Akiyama, Atsushi Takahashi, Satoshi Koyama, Seitaro Nomura, Hirotaka Ieki, Kouichi Ozaki, Yoshihiro Onouchi, Saori Sakaue, Shinichiro Suna, Soichi Ogishima, Masayuki Yamamoto, Atsushi Hozawa, Mamoru Satoh, Makoto Sasaki, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Shoichiro Tsugane, Keitaro Tanaka, Kokichi Arisawa, Hiroaki Ikezaki, Naoyuki Takashima, Mariko Naito, Kenji Wakai, Hideo Tanaka, Yasuhiko Sakata, Hiroyuki Morita, Yasushi Sakata, Koichi Matsuda, Yoshinori Murakami, Hiroshi Akazawa, Michiaki Kubo, Yoichiro Kamatani, Issei Komuro, Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease., Circulation. Genomic and precision medicine, 10.1161/CIRCGEN.119.002670, 13, 3, e002670, 2020.06, BACKGROUND: Genome-wide association studies provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. Genome-wide association studies in diverse populations have the potential to advance our understanding of CAD. METHODS: We conducted 2 genome-wide association studies for CAD in the Japanese population, which included 12 494 cases and 28 879 controls and 2808 cases and 7261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the coronary artery disease genome-wide replication and meta-analysis plus the coronary artery disease 1000 Genomes meta-analysis with UK Biobank. We then explored the pathophysiological significance of these novel loci and examined the differences in CAD-susceptibility loci between Japanese and Europeans. RESULTS: We identified 3 new loci on chromosome 1q21 (CTSS), 10q26 (WDR11-FGFR2), and 11q22 (RDX-FDX1). Quantitative trait locus analyses suggested the association of CTSS and RDX-FDX1 with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands, and fat tissues in the development of CAD. We next compared the odds ratios of lead variants for myocardial infarction at 76 genome-wide significant loci in the transethnic meta-analysis and a moderate correlation between Japanese and Europeans, where 8 loci showed a difference. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans. CONCLUSIONS: We identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully..
42. Ming-Huei Chen, Laura M Raffield, Abdou Mousas, Saori Sakaue, Jennifer E Huffman, Arden Moscati, Bhavi Trivedi, Tao Jiang, Parsa Akbari, Dragana Vuckovic, Erik L Bao, Xue Zhong, Regina Manansala, Véronique Laplante, Minhui Chen, Ken Sin Lo, Huijun Qian, Caleb A Lareau, Mélissa Beaudoin, Karen A Hunt, Masato Akiyama, Traci M Bartz, Yoav Ben-Shlomo, Andrew Beswick, Jette Bork-Jensen, Erwin P Bottinger, Jennifer A Brody, Frank J A van Rooij, Kumaraswamynaidu Chitrala, Kelly Cho, Hélène Choquet, Adolfo Correa, John Danesh, Emanuele Di Angelantonio, Niki Dimou, Jingzhong Ding, Paul Elliott, Tõnu Esko, Michele K Evans, James S Floyd, Linda Broer, Niels Grarup, Michael H Guo, Andreas Greinacher, Jeff Haessler, Torben Hansen, Joanna M M Howson, Qin Qin Huang, Wei Huang, Eric Jorgenson, Tim Kacprowski, Mika Kähönen, Yoichiro Kamatani, Masahiro Kanai, Savita Karthikeyan, Fotis Koskeridis, Leslie A Lange, Terho Lehtimäki, Markus M Lerch, Allan Linneberg, Yongmei Liu, Leo-Pekka Lyytikäinen, Ani Manichaikul, Hilary C Martin, Koichi Matsuda, Karen L Mohlke, Nina Mononen, Yoshinori Murakami, Girish N Nadkarni, Matthias Nauck, Kjell Nikus, Willem H Ouwehand, Nathan Pankratz, Oluf Pedersen, Michael Preuss, Bruce M Psaty, Olli T Raitakari, David J Roberts, Stephen S Rich, Benjamin A T Rodriguez, Jonathan D Rosen, Jerome I Rotter, Petra Schubert, Cassandra N Spracklen, Praveen Surendran, Hua Tang, Jean-Claude Tardif, Richard C Trembath, Mohsen Ghanbari, Uwe Völker, Henry Völzke, Nicholas A Watkins, Alan B Zonderman, Peter W F Wilson, Yun Li, Adam S Butterworth, Jean-François Gauchat, Charleston W K Chiang, Bingshan Li, Ruth J F Loos, William J Astle, Evangelos Evangelou, David A van Heel, Vijay G Sankaran, Yukinori Okada, Nicole Soranzo, Andrew D Johnson, Alexander P Reiner, Paul L Auer, Guillaume Lettre, Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations., Cell, 10.1016/j.cell.2020.06.045, 182, 5, 1198-1213, 2020.09, Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies..
43. Saori Sakaue, Masahiro Kanai, Juha Karjalainen, Masato Akiyama, Mitja Kurki, Nana Matoba, Atsushi Takahashi, Makoto Hirata, Michiaki Kubo, Koichi Matsuda, Yoshinori Murakami, Mark J Daly, Yoichiro Kamatani, Yukinori Okada, Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan., Nature medicine, 10.1038/s41591-020-0785-8, 26, 4, 542-548, 2020.04, While polygenic risk scores (PRSs) are poised to be translated into clinical practice through prediction of inborn health risks1, a strategy to utilize genetics to prioritize modifiable risk factors driving heath outcome is warranted2. To this end, we investigated the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (ntotal = 675,898; BioBank Japan (n = 179,066), UK Biobank (n = 361,194) and FinnGen (n = 135,638)). In contrast to observational studies, in which discerning the cause-and-effect can be difficult, PRSs could help to identify the driver biomarkers affecting human lifespan. A high systolic blood pressure PRS was trans-ethnically associated with a shorter lifespan (hazard ratio = 1.03[1.02-1.04], Pmeta = 3.9 × 10-13) and parental lifespan (hazard ratio = 1.06[1.06-1.07], P = 2.0 × 10-86). The obesity PRS showed distinct effects on lifespan in Japanese and European individuals (Pheterogeneity = 9.5 × 10-8 for BMI). The causal effect of blood pressure and obesity on lifespan was further supported by Mendelian randomization studies. Beyond genotype-phenotype associations, our trans-biobank study offers a new value of PRSs in prioritization of risk factors that could be potential targets of medical treatment to improve population health..
44. Dragana Vuckovic, Erik L Bao, Parsa Akbari, Caleb A Lareau, Abdou Mousas, Tao Jiang, Ming-Huei Chen, Laura M Raffield, Manuel Tardaguila, Jennifer E Huffman, Scott C Ritchie, Karyn Megy, Hannes Ponstingl, Christopher J Penkett, Patrick K Albers, Emilie M Wigdor, Saori Sakaue, Arden Moscati, Regina Manansala, Ken Sin Lo, Huijun Qian, Masato Akiyama, Traci M Bartz, Yoav Ben-Shlomo, Andrew Beswick, Jette Bork-Jensen, Erwin P Bottinger, Jennifer A Brody, Frank J A van Rooij, Kumaraswamy N Chitrala, Peter W F Wilson, Hélène Choquet, John Danesh, Emanuele Di Angelantonio, Niki Dimou, Jingzhong Ding, Paul Elliott, Tõnu Esko, Michele K Evans, Stephan B Felix, James S Floyd, Linda Broer, Niels Grarup, Michael H Guo, Qi Guo, Andreas Greinacher, Jeff Haessler, Torben Hansen, Joanna M M Howson, Wei Huang, Eric Jorgenson, Tim Kacprowski, Mika Kähönen, Yoichiro Kamatani, Masahiro Kanai, Savita Karthikeyan, Fotios Koskeridis, Leslie A Lange, Terho Lehtimäki, Allan Linneberg, Yongmei Liu, Leo-Pekka Lyytikäinen, Ani Manichaikul, Koichi Matsuda, Karen L Mohlke, Nina Mononen, Yoshinori Murakami, Girish N Nadkarni, Kjell Nikus, Nathan Pankratz, Oluf Pedersen, Michael Preuss, Bruce M Psaty, Olli T Raitakari, Stephen S Rich, Benjamin A T Rodriguez, Jonathan D Rosen, Jerome I Rotter, Petra Schubert, Cassandra N Spracklen, Praveen Surendran, Hua Tang, Jean-Claude Tardif, Mohsen Ghanbari, Uwe Völker, Henry Völzke, Nicholas A Watkins, Stefan Weiss, Na Cai, Kousik Kundu, Stephen B Watt, Klaudia Walter, Alan B Zonderman, Kelly Cho, Yun Li, Ruth J F Loos, Julian C Knight, Michel Georges, Oliver Stegle, Evangelos Evangelou, Yukinori Okada, David J Roberts, Michael Inouye, Andrew D Johnson, Paul L Auer, William J Astle, Alexander P Reiner, Adam S Butterworth, Willem H Ouwehand, Guillaume Lettre, Vijay G Sankaran, Nicole Soranzo, The Polygenic and Monogenic Basis of Blood Traits and Diseases., Cell, 10.1016/j.cell.2020.08.008, 182, 5, 1214-1231, 2020.09, Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation..
45. Toshiharu Ninomiya, Shigeyuki Nakaji, Tetsuya Maeda, Masahito Yamada, Masaru Mimura, Kenji Nakashima, Takaaki Mori, Minoru Takebayashi, Tomoyuki Ohara, Jun Hata, Yoshihiro Kokubo, Kazuhiro Uchida, Yasuyuki Taki, Shuzo Kumagai, Koji Yonemoto, Hisako Yoshida, Kaori Muto, Yukihide Momozawa, Masato Akiyama, Michiaki Kubo, Manabu Ikeda, Shigenobu Kanba, Yutaka Kiyohara, Study design and baseline characteristics of a population-based prospective cohort study of dementia in Japan: the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD)., Environmental health and preventive medicine, 10.1186/s12199-020-00903-3, 25, 1, 64-64, 2020.10, BACKGROUND: The burden of dementia is growing rapidly and has become a medical and social problem in Japan. Prospective cohort studies have been considered an effective methodology to clarify the risk factors and the etiology of dementia. We aimed to perform a large-scale dementia cohort study to elucidate environmental and genetic risk factors for dementia, as well as their interaction. METHODS: The Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) is a multisite, population-based prospective cohort study of dementia, which was designed to enroll approximately 10,000 community-dwelling residents aged 65 years or older from 8 sites in Japan and to follow them up prospectively for at least 5 years. Baseline exposure data, including lifestyles, medical information, diets, physical activities, blood pressure, cognitive function, blood test, brain magnetic resonance imaging (MRI), and DNA samples, were collected with a pre-specified protocol and standardized measurement methods. The primary outcome was the development of dementia and its subtypes. The diagnosis of dementia was adjudicated by an endpoint adjudication committee using standard criteria and clinical information according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition. For brain MRI, three-dimensional acquisition of T1-weighted images was performed. Individual participant data were pooled for data analyses. RESULTS: The baseline survey was conducted from 2016 to 2018. The follow-up surveys are ongoing. A total of 11,410 individuals aged 65 years or older participated in the study. The mean age was 74.4 years, and 41.9% were male. The prevalence of dementia at baseline was 8.5% in overall participants. However, it was 16.4% among three sites where additional home visit and/or nursing home visit surveys were performed. Approximately two-thirds of dementia cases at baseline were Alzheimer's disease. CONCLUSIONS: The prospective cohort data from the JPSC-AD will provide valuable insights regarding the risk factors and etiology of dementia as well as for the development of predictive models and diagnostic markers for the future onset of dementia. The findings of this study will improve our understanding of dementia and provide helpful information to establish effective preventive strategies for dementia in Japan..
46. Yoshito Koyanagi, Shinji Ueno, Yasuki Ito, Taro Kominami, Shiori Komori, Masato Akiyama, Yusuke Murakami, Yasuhiro Ikeda, Koh-Hei Sonoda, Hiroko Terasaki, Relationship Between Macular Curvature and Common Causative Genes of Retinitis Pigmentosa in Japanese Patients., Investigative ophthalmology & visual science, 10.1167/iovs.61.10.6, 61, 10, 6-6, 2020.08, Purpose: To determine the relationship between the macular curvature and the causative genes of retinitis pigmentosa (RP). Methods: We examined the medical records of the right eyes of 65 cases with RP (31 men and 34 women; average age, 47.6 years). There were 31 cases with the EYS variants, 11 cases with the USH2A variants, six cases with the RPGR variants, 13 cases with the RP1 variants, and four cases with the RP1L1 variants. The mean curvature of Bruch's membrane was calculated within 6 mm of the fovea as the mean macular curvature index (MMCI, 1/µm). We used multiple linear regression analysis to determine the independence of the causative genes contributing to the MMCIs after adjustments for age, sex, axial length, and width of the ellipsoid zone. Results: The median MMCI was -31.2 × 10-5/µm for the RPGR eyes, -16.5 × 10-5/µm for the RP1L1 eyes, -13.0 × 10-5/µm for the RP1 eyes, -9.8 × 10-5/µm for the EYS eyes, and -9.0 × 10-5/µm for the USH2A eyes. Compared with the EYS gene as the reference gene, the RPGR gene was significantly related to the MMCI values after adjusting for the other parameters (P = 5.30 × 10-6). In contrast, the effects of the other genes, USH2A, RP1, and RP1L1, were not significantly different from that of the EYS gene (P = 0.26, P = 0.49, and P = 0.92, respectively). Conclusions: The RPGR gene had a stronger effect on the steep macular curvature than the other ciliopathy-related genes..
47. Satoshi Koyama, Kaoru Ito, Chikashi Terao, Masato Akiyama, Momoko Horikoshi, Yukihide Momozawa, Hiroshi Matsunaga, Hirotaka Ieki, Kouichi Ozaki, Yoshihiro Onouchi, Atsushi Takahashi, Seitaro Nomura, Hiroyuki Morita, Hiroshi Akazawa, Changhoon Kim, Jeong-Sun Seo, Koichiro Higasa, Motoki Iwasaki, Taiki Yamaji, Norie Sawada, Shoichiro Tsugane, Teruhide Koyama, Hiroaki Ikezaki, Naoyuki Takashima, Keitaro Tanaka, Kokichi Arisawa, Kiyonori Kuriki, Mariko Naito, Kenji Wakai, Shinichiro Suna, Yasuhiko Sakata, Hiroshi Sato, Masatsugu Hori, Yasushi Sakata, Koichi Matsuda, Yoshinori Murakami, Hiroyuki Aburatani, Michiaki Kubo, Fumihiko Matsuda, Yoichiro Kamatani, Issei Komuro, Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease., Nature genetics, 10.1038/s41588-020-0705-3, 52, 11, 1169-1177, 2020.11, To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study of 168,228 individuals of Japanese ancestry (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,781 CAD cases and 2,636 controls. We detected eight new susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a trans-ancestry meta-analysis and discovered 35 additional new loci. Using the meta-analysis results, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European genome-wide association studies. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improve the clinical characterization of CAD genetics and suggest the utility of trans-ancestry meta-analysis for PRS derivation in non-European populations..
48. Yoshihiro Kaizu, Shintaro Nakao, Iori Wada, Mitsuru Arima, Muneo Yamaguchi, Keijiro Ishikawa, Masato Akiyama, Junji Kishimoto, Toshio Hisatomi, Koh-Hei Sonoda, Microaneurysm Imaging Using Multiple En Face OCT Angiography Image Averaging: Morphology and Visualization., Ophthalmology. Retina, 10.1016/j.oret.2019.09.010, 4, 2, 175-186, 2020.02, PURPOSE: In diabetic retinopathy (DR), OCT angiography (OCTA) could not image all fluorescein angiography (FA)-detected microaneurysms. We investigated whether multiple image averaging could enhance the microaneurysm detection capability of OCTA in patients with DR. DESIGN: Prospective and cross-sectional observational study. PARTICIPANTS: Consecutive 31 patients (n = 62 eyes) with DR. METHODS: All eyes underwent FA and 3 × 3 mm fovea-centered OCTA images were obtained using 2 devices: RTVue XR Avanti (Optovue Inc, Fremont, CA) and OCT HS-100 (Canon Inc, Toyko, Japan). OCTA imaging (HS-100) was performed 10 consecutive times. Microaneurysm detection capability was compared among 5 OCTA images (single image, ×3, ×5, and ×10 averaged images and single scan image with the RTVue XR Avanti device). MAIN OUTCOME MEASURES: Microaneurysm detection capability and the correlation between microaneurysm clinical characteristics or morphology and the extent of image averaging required for OCTA detection. RESULTS: A total of 415 microaneurysms could be analyzed in 31 eyes from 25 patients. Microaneurysms detected on single image, ×3, ×5, and ×10 averaged OCTA images were 144 (34.7%), 227 (54.7%), 285 (68.7%), and 306 (73.7%), respectively. Microaneurysm detection capability was significantly increased with increased image averaging. Microaneurysm detection with OCTA was not correlated with retinal thickness, FA leakiness, and indocyanine green angiogram detection or the number of averaged images, whereas there was significant correlation between microaneurysm morphology and microaneurysm visibility by the image-averaging process for 4 morphologies, particular the focal bulge types (P < 0.01). CONCLUSIONS: In DR, multiple image averaging is useful for increasing the microaneurysm detection capability of OCTA, especially for focal bulge-type microaneurysms..
49. Yan Zheng, Tao Huang, Tiange Wang, Zhendong Mei, Zhonghan Sun, Tao Zhang, Christina Ellervik, Jin-Fang Chai, Xueling Sim, Rob M van Dam, E-Shyong Tai, Woon-Puay Koh, Rajkumar Dorajoo, Seang-Mei Saw, Charumathi Sabanayagam, Tien Yin Wong, Preeti Gupta, Peter Rossing, Tarunveer S Ahluwalia, Rebecca K Vinding, Hans Bisgaard, Klaus Bønnelykke, Yujie Wang, Mariaelisa Graff, Trudy Voortman, Frank J A van Rooij, Albert Hofman, Diana van Heemst, Raymond Noordam, Angela C Estampador, Tibor V Varga, Cornelia Enzenbach, Markus Scholz, Joachim Thiery, Ralph Burkhardt, Marju Orho-Melander, Christina-Alexandra Schulz, Ulrika Ericson, Emily Sonestedt, Michiaki Kubo, Masato Akiyama, Ang Zhou, Tuomas O Kilpeläinen, Torben Hansen, Marcus E Kleber, Graciela Delgado, Mark McCarthy, Rozenn N Lemaitre, Janine F Felix, Vincent W V Jaddoe, Ying Wu, Karen L Mohlke, Terho Lehtimäki, Carol A Wang, Craig E Pennell, Heribert Schunkert, Thorsten Kessler, Lingyao Zeng, Christina Willenborg, Annette Peters, Wolfgang Lieb, Veit Grote, Peter Rzehak, Berthold Koletzko, Jeanette Erdmann, Matthias Munz, Tangchun Wu, Meian He, Caizheng Yu, Cécile Lecoeur, Philippe Froguel, Dolores Corella, Luis A Moreno, Chao-Qiang Lai, Niina Pitkänen, Colin A Boreham, Paul M Ridker, Frits R Rosendaal, Renée de Mutsert, Chris Power, Lavinia Paternoster, Thorkild I A Sørensen, Anne Tjønneland, Kim Overvad, Luc Djousse, Fernando Rivadeneira, Nanette R Lee, Olli T Raitakari, Mika Kähönen, Jorma Viikari, Jean-Paul Langhendries, Joaquin Escribano, Elvira Verduci, George Dedoussis, Inke König, Beverley Balkau, Oscar Coltell, Jean Dallongeville, Aline Meirhaeghe, Philippe Amouyel, Frédéric Gottrand, Katja Pahkala, Harri Niinikoski, Elina Hyppönen, Winfried März, David A Mackey, Dariusz Gruszfeld, Katherine L Tucker, Frédéric Fumeron, Ramon Estruch, Jose M Ordovas, Donna K Arnett, Dennis O Mook-Kanamori, Dariush Mozaffarian, Bruce M Psaty, Kari E North, Daniel I Chasman, Lu Qi, Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood., European journal of epidemiology, 10.1007/s10654-020-00638-z, 35, 7, 685-697, 2020.07, Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses..
50. Kazuyoshi Ishigaki, Masato Akiyama, Masahiro Kanai, Atsushi Takahashi, Eiryo Kawakami, Hiroki Sugishita, Saori Sakaue, Nana Matoba, Siew-Kee Low, Yukinori Okada, Chikashi Terao, Tiffany Amariuta, Steven Gazal, Yuta Kochi, Momoko Horikoshi, Ken Suzuki, Kaoru Ito, Satoshi Koyama, Kouichi Ozaki, Shumpei Niida, Yasushi Sakata, Yasuhiko Sakata, Takashi Kohno, Kouya Shiraishi, Yukihide Momozawa, Makoto Hirata, Koichi Matsuda, Masashi Ikeda, Nakao Iwata, Shiro Ikegawa, Ikuyo Kou, Toshihiro Tanaka, Hidewaki Nakagawa, Akari Suzuki, Tomomitsu Hirota, Mayumi Tamari, Kazuaki Chayama, Daiki Miki, Masaki Mori, Satoshi Nagayama, Yataro Daigo, Yoshio Miki, Toyomasa Katagiri, Osamu Ogawa, Wataru Obara, Hidemi Ito, Teruhiko Yoshida, Issei Imoto, Takashi Takahashi, Chizu Tanikawa, Takao Suzuki, Nobuaki Sinozaki, Shiro Minami, Hiroki Yamaguchi, Satoshi Asai, Yasuo Takahashi, Ken Yamaji, Kazuhisa Takahashi, Tomoaki Fujioka, Ryo Takata, Hideki Yanai, Akihide Masumoto, Yukihiro Koretsune, Hiromu Kutsumi, Masahiko Higashiyama, Shigeo Murayama, Naoko Minegishi, Kichiya Suzuki, Kozo Tanno, Atsushi Shimizu, Taiki Yamaji, Motoki Iwasaki, Norie Sawada, Hirokazu Uemura, Keitaro Tanaka, Mariko Naito, Makoto Sasaki, Kenji Wakai, Shoichiro Tsugane, Masayuki Yamamoto, Kazuhiko Yamamoto, Yoshinori Murakami, Yusuke Nakamura, Soumya Raychaudhuri, Johji Inazawa, Toshimasa Yamauchi, Takashi Kadowaki, Michiaki Kubo, Yoichiro Kamatani, Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases., Nature genetics, 10.1038/s41588-020-0640-3, 52, 7, 669-679, 2020.07, The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations..
51. Keijiro Ishikawa, Ri-Ichiro Kohno, Kenichiro Mori, Yusuke Murakami, Shintaro Nakao, Masato Akiyama, Shigeo Yoshida, Koh-Hei Sonoda, Increased expression of periostin and tenascin-C in eyes with neovascular glaucoma secondary to PDR., Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 10.1007/s00417-019-04574-x, 258, 3, 621-628, 2020.03, PURPOSE: To investigate periostin (PN) and tenascin-C (TNC) expression in the aqueous humor and trabeculectomy specimens of patients with neovascular glaucoma (NVG) secondary to proliferative diabetic retinopathy (PDR). METHODS: This study enrolled 37 eyes of 37 patients who were grouped into (1) NVG secondary to PDR (NVG; n = 8); (2) PDR without NVG (PDR; n = 9); (3) primary open-angle glaucoma (POAG; n = 11); and (4) cataract surgery patients as a control group (CG; n = 9). Aqueous humor samples were collected from the anterior chamber at the start of surgery or intravitreal injection of anti-VEGF drug. The concentrations of PN, TNC, VEGF, and TGF-β2 (transforming growth factor-beta 2) were measured by ELISA. Sclerostomy tissues containing trabecular meshwork were obtained from two NVG patients and a POAG patient who underwent trabeculectomy surgery. Immunohistochemical analyses were performed to determine the localization of PN and TNC expression in the sclerostomy tissues. RESULTS: PN and TNC-C levels were below detection threshold in the POAG and CG groups. The NVG group had significantly higher levels of PN and TNC compared with the PDR group (84.7 ng/ml vs 2.2 ng/ml and 18.5 ng/ml vs 4.6 ng/ml, respectively; p < 0.05). There was a significant correlation between the levels of PN and TNC-C in the NVG group (r = 0.86, p < 0.05). We found significant expression of PN in the trabecular meshwork and Schlemm's canal of sclerostomy tissues excised from patients with NVG. CONCLUSIONS: Increased PN and TNC expression suggests their possible involvement in the pathogenesis of NVG secondary to PDR..
52. Cassandra N Spracklen, Momoko Horikoshi, Young Jin Kim, Kuang Lin, Fiona Bragg, Sanghoon Moon, Ken Suzuki, Claudia H T Tam, Yasuharu Tabara, Soo-Heon Kwak, Fumihiko Takeuchi, Jirong Long, Victor J Y Lim, Jin-Fang Chai, Chien-Hsiun Chen, Masahiro Nakatochi, Jie Yao, Hyeok Sun Choi, Apoorva K Iyengar, Hannah J Perrin, Sarah M Brotman, Martijn van de Bunt, Anna L Gloyn, Jennifer E Below, Michael Boehnke, Donald W Bowden, John C Chambers, Anubha Mahajan, Mark I McCarthy, Maggie C Y Ng, Lauren E Petty, Weihua Zhang, Andrew P Morris, Linda S Adair, Masato Akiyama, Zheng Bian, Juliana C N Chan, Li-Ching Chang, Miao-Li Chee, Yii-Der Ida Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Shufa Du, Penny Gordon-Larsen, Myron Gross, Xiuqing Guo, Yu Guo, Sohee Han, Annie-Green Howard, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Masato Isono, Hye-Mi Jang, Guozhi Jiang, Jost B Jonas, Yoichiro Kamatani, Tomohiro Katsuya, Takahisa Kawaguchi, Chiea-Chuen Khor, Katsuhiko Kohara, Myung-Shik Lee, Nanette R Lee, Liming Li, Jianjun Liu, Andrea O Luk, Jun Lv, Yukinori Okada, Mark A Pereira, Charumathi Sabanayagam, Jinxiu Shi, Dong Mun Shin, Wing Yee So, Atsushi Takahashi, Brian Tomlinson, Fuu-Jen Tsai, Rob M van Dam, Yong-Bing Xiang, Ken Yamamoto, Toshimasa Yamauchi, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Liang Zhang, Wei Zheng, Michiya Igase, Yoon Shin Cho, Jerome I Rotter, Ya-Xing Wang, Wayne H H Sheu, Mitsuhiro Yokota, Jer-Yuarn Wu, Ching-Yu Cheng, Tien-Yin Wong, Xiao-Ou Shu, Norihiro Kato, Kyong-Soo Park, E-Shyong Tai, Fumihiko Matsuda, Woon-Puay Koh, Ronald C W Ma, Shiro Maeda, Iona Y Millwood, Juyoung Lee, Takashi Kadowaki, Robin G Walters, Bong-Jo Kim, Karen L Mohlke, Xueling Sim, Identification of type 2 diabetes loci in 433,540 East Asian individuals., Nature, 10.1038/s41586-020-2263-3, 582, 7811, 240-245, 2020.06, Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways..
53. Yingsong Lin, Masahiro Nakatochi, Yasuyuki Hosono, Hidemi Ito, Yoichiro Kamatani, Akihito Inoko, Hiromi Sakamoto, Fumie Kinoshita, Yumiko Kobayashi, Hiroshi Ishii, Masato Ozaka, Takashi Sasaki, Masato Matsuyama, Naoki Sasahira, Manabu Morimoto, Satoshi Kobayashi, Taito Fukushima, Makoto Ueno, Shinichi Ohkawa, Naoto Egawa, Sawako Kuruma, Mitsuru Mori, Haruhisa Nakao, Yasushi Adachi, Masumi Okuda, Takako Osaki, Shigeru Kamiya, Chaochen Wang, Kazuo Hara, Yasuhiro Shimizu, Tatsuo Miyamoto, Yuko Hayashi, Hiromichi Ebi, Tomohiro Kohmoto, Issei Imoto, Yumiko Kasugai, Yoshinori Murakami, Masato Akiyama, Kazuyoshi Ishigaki, Koichi Matsuda, Makoto Hirata, Kazuaki Shimada, Takuji Okusaka, Takahisa Kawaguchi, Meiko Takahashi, Yoshiyuki Watanabe, Kiyonori Kuriki, Aya Kadota, Rieko Okada, Haruo Mikami, Toshiro Takezaki, Sadao Suzuki, Taiki Yamaji, Motoki Iwasaki, Norie Sawada, Atsushi Goto, Kengo Kinoshita, Nobuo Fuse, Fumiki Katsuoka, Atsushi Shimizu, Satoshi S Nishizuka, Kozo Tanno, Ken Suzuki, Yukinori Okada, Momoko Horikoshi, Toshimasa Yamauchi, Takashi Kadowaki, Herbert Yu, Jun Zhong, Laufey T Amundadottir, Yuichiro Doki, Hideshi Ishii, Hidetoshi Eguchi, David Bogumil, Christopher A Haiman, Loic Le Marchand, Masaki Mori, Harvey Risch, Veronica W Setiawan, Shoichiro Tsugane, Kenji Wakai, Teruhiko Yoshida, Fumihiko Matsuda, Michiaki Kubo, Shogo Kikuchi, Keitaro Matsuo, Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer., Nature communications, 10.1038/s41467-020-16711-w, 11, 1, 3175-3175, 2020.06, Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10-8), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry..
54. Mark K Bakker, Rick A A van der Spek, Wouter van Rheenen, Sandrine Morel, Romain Bourcier, Isabel C Hostettler, Varinder S Alg, Kristel R van Eijk, Masaru Koido, Masato Akiyama, Chikashi Terao, Koichi Matsuda, Robin G Walters, Kuang Lin, Liming Li, Iona Y Millwood, Zhengming Chen, Guy A Rouleau, Sirui Zhou, Kristiina Rannikmäe, Cathie L M Sudlow, Henry Houlden, Leonard H van den Berg, Christian Dina, Olivier Naggara, Jean-Christophe Gentric, Eimad Shotar, François Eugène, Hubert Desal, Bendik S Winsvold, Sigrid Børte, Marianne Bakke Johnsen, Ben M Brumpton, Marie Søfteland Sandvei, Cristen J Willer, Kristian Hveem, John-Anker Zwart, W M Monique Verschuren, Christoph M Friedrich, Sven Hirsch, Sabine Schilling, Jérôme Dauvillier, Olivier Martin, Gregory T Jones, Matthew J Bown, Nerissa U Ko, Helen Kim, Jonathan R I Coleman, Gerome Breen, Jonathan G Zaroff, Catharina J M Klijn, Rainer Malik, Martin Dichgans, Muralidharan Sargurupremraj, Turgut Tatlisumak, Philippe Amouyel, Stéphanie Debette, Gabriel J E Rinkel, Bradford B Worrall, Joanna Pera, Agnieszka Slowik, Emília I Gaál-Paavola, Mika Niemelä, Juha E Jääskeläinen, Mikael von Und Zu Fraunberg, Antti Lindgren, Joseph P Broderick, David J Werring, Daniel Woo, Richard Redon, Philippe Bijlenga, Yoichiro Kamatani, Jan H Veldink, Ynte M Ruigrok, Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors., Nature genetics, 10.1038/s41588-020-00725-7, 52, 12, 1303-1313, 2020.12, Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits..
55. Fumihiko Mabuchi, Nakako Mabuchi, Yoichi Sakurada, Seigo Yoneyama, Kenji Kashiwagi, Hiroyuki Iijima, Zentaro Yamagata, Mitsuko Takamoto, Makoto Aihara, Takeshi Iwata, Kazuki Hashimoto, Kota Sato, Yukihiro Shiga, Koji M Nishiguchi, Toru Nakazawa, Masato Akiyama, Kazuhide Kawase, Mineo Ozaki, Makoto Araie, Genetic Variants Associated With the Onset and Progression of Primary Open-Angle Glaucoma., American journal of ophthalmology, 10.1016/j.ajo.2020.03.014, 215, 135-140, 2020.07, PURPOSE: We sought to investigate the genetic variants associated with the onset and progression of primary open-angle glaucoma (POAG). DESIGN: Case-control genetic association study. METHODS: Japanese POAG patients (n = 505) and control subjects (n = 246) were genotyped for 22 genetic variants predisposing to POAG that can be classified into those associated with intraocular pressure (IOP) elevation (IOP-related genetic variants) and optic nerve vulnerability independent of IOP (non-IOP-related genetic variants). The total number of risk alleles of the 17 IOP-related and 5 non-IOP-related genetic variants were calculated as the genetic risk score (GRS), and the associations between the GRS and family history of glaucoma as an indicator of POAG onset and age at the diagnosis of glaucoma as an indicator of POAG progression were evaluated. RESULTS: There was a significant association (P = .014; odds ratio 1.26 per GRS) between the non-IOP-related GRS, but not IOP-related GRS, and a family history of glaucoma in POAG. As the non-IOP-related GRS increased, the risk of a family history of glaucoma increased. In contrast, a significant association (P = .0014; β = -0.14) was found between the IOP-related GRS, but not non-IOP-related GRS, and age at the diagnosis of glaucoma. As the IOP-related GRS increased, age at the diagnosis of glaucoma decreased. CONCLUSION: The results indicate that non-IOP-related (optic nerve vulnerability) rather than IOP-related (IOP elevation) genetic variants may play an important role in the onset of POAG (family history of glaucoma) and that IOP-related rather than non-IOP-related genetic variants may play an important role in its progression (age at the diagnosis of glaucoma)..
56. Tatsuo Masuda, Siew-Kee Low, Masato Akiyama, Makoto Hirata, Yutaka Ueda, Koichi Matsuda, Tadashi Kimura, Yoshinori Murakami, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, GWAS of five gynecologic diseases and cross-trait analysis in Japanese., European journal of human genetics : EJHG, 10.1038/s41431-019-0495-1, 28, 1, 95-107, 2020.01, We performed genome-wide association studies of five gynecologic diseases using data of 46,837 subjects (5236 uterine fibroid, 645 endometriosis, 647 ovarian cancer (OC), 909 uterine endometrial cancer (UEC), and 538 uterine cervical cancer (UCC) cases allowing overlaps, and 39,556 shared female controls) from Biobank Japan Project. We used the population-specific imputation reference panel (n = 3541), yielding 7,645,193 imputed variants. Analyses performed under logistic model, linear mixed model, and model incorporating correlations identified nine significant associations with three gynecologic diseases including four novel findings (rs79219469:C > T, LINC02183, P = 3.3 × 10-8 and rs567534295:C > T, BRCA1, P = 3.1 × 10-8 with OC, rs150806792:C > T, INS-IGF2, P = 4.9 × 10-8 and rs140991990:A > G, SOX9, P = 3.3 × 10-8 with UCC). Random-effect meta-analysis of the five GWASs correcting for the overlapping subjects suggested one novel shared risk locus (rs937380553:A > G, LOC730100, P = 2.0 × 10-8). Reverse regression analysis identified three additional novel associations (rs73494486:C > T, GABBR2, P = 4.8 × 10-8, rs145152209:A > G, SH3GL3/BNC1, P = 3.3 × 10-8, and rs147427629:G > A, LOC107985484, P = 3.8 × 10-8). Estimated heritability ranged from 0.026 for OC to 0.220 for endometriosis. Genetic correlations were relatively strong between OC and UEC, endometriosis and OC, and uterine fibroid and OC (rg > 0.79) compared with relatively weak correlations between UCC and the other four (rg = -0.08 ~ 0.25). We successfully identified genetic associations with gynecologic diseases in the Japanese population. Shared genetic effects among multiple related diseases may help understanding the pathophysiology..
57. Nana Matoba, Masato Akiyama, Kazuyoshi Ishigaki, Masahiro Kanai, Atsushi Takahashi, Yukihide Momozawa, Shiro Ikegawa, Masashi Ikeda, Nakao Iwata, Makoto Hirata, Koichi Matsuda, Yoshinori Murakami, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, GWAS of 165,084 Japanese individuals identified nine loci associated with dietary habits., Nature human behaviour, 10.1038/s41562-019-0805-1, 4, 3, 308-316, 2020.03, Dietary habits are important factors in our lifestyle, and confer both susceptibility to and protection from a variety of human diseases. We performed genome-wide association studies for 13 dietary habits including consumption of alcohol (ever versus never drinkers and drinks per week), beverages (coffee, green tea and milk) and foods (yoghurt, cheese, natto, tofu, fish, small whole fish, vegetables and meat) in Japanese individuals (n = 58,610-165,084) collected by BioBank Japan, the nationwide hospital-based genome cohort. Significant associations were found in nine genetic loci (MCL1-ENSA, GCKR, AGR3-AHR, ADH1B, ALDH1B1, ALDH1A1, ALDH2, CYP1A2-CSK and ADORA2A-AS1) for 13 dietary traits (P < 3.8 × 10-9). Of these, ten associations between five loci and eight traits were new findings. Furthermore, a phenome-wide association study revealed that five of the dietary trait-associated loci have pleiotropic effects on multiple human complex diseases and clinical measurements. Our findings provide new insight into the genetics of habitual consumption..
58. Saori Sakaue, Masato Akiyama, Makoto Hirata, Koichi Matsuda, Yoshinori Murakami, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Functional variants in ADH1B and ALDH2 are non-additively associated with all-cause mortality in Japanese population., European journal of human genetics : EJHG, 10.1038/s41431-019-0518-y, 28, 3, 378-382, 2020.03, The functional variants involved in alcohol metabolism, the A allele of rs1229984:A > G in ADH1B and the A allele of rs671:G > A in ALDH2, are specifically prevalent among East Asian population. They are shown to be under recent positive selection, but the reasons for the selection are unknown. To test whether these positively selected variants have beneficial effects on survival in modern population, we performed the survival analyses using the large-scale Japanese cohort (n = 135,974) with genotype and follow-up survival data. The rs671-A allele was significantly associated with the better survival in the additive model (HR for mortality = 0.960, P = 1.7 × 10-5), and the rs1229984-A had both additive and non-additive effects (HR = 0.962, P = 0.0016 and HR = 0.958, P = 0.0066, respectively), which was consistent with the positive selection. The favorable effects of these alleles on survival were independent of the habit of alcohol consumption itself. The heterogenous combinatory effect between rs1229984 and rs671 genotype was also observed (HRs for AA genotype at rs671 were 1.03, 0.80, and 0.90 for GG, GA, and AA genotype at rs1229984, respectively), supposedly reflecting the synergistic effects on survival..
59. Minhui Chen, Carlo Sidore, Masato Akiyama, Kazuyoshi Ishigaki, Yoichiro Kamatani, David Schlessinger, Francesco Cucca, Yukinori Okada, Charleston W K Chiang, Evidence of Polygenic Adaptation in Sardinia at Height-Associated Loci Ascertained from the Biobank Japan., American journal of human genetics, 10.1016/j.ajhg.2020.05.014, 107, 1, 60-71, 2020.07, Adult height is one of the earliest putative examples of polygenic adaptation in humans. However, this conclusion was recently challenged because residual uncorrected stratification from large-scale consortium studies was considered responsible for the previously noted genetic difference. It thus remains an open question whether height loci exhibit signals of polygenic adaptation in any human population. We re-examined this question, focusing on one of the shortest European populations, the Sardinians, in addition to mainland European populations. We utilized height-associated loci from the Biobank Japan (BBJ) dataset to further alleviate concerns of biased ascertainment of GWAS loci and showed that the Sardinians remain significantly shorter than expected under neutrality (∼0.22 standard deviation shorter than Utah residents with ancestry from northern and western Europe [CEU] on the basis of polygenic height scores, p = 3.89 × 10-4). We also found the trajectory of polygenic height scores between the Sardinian and the British populations diverged over at least the last 10,000 years (p = 0.0082), consistent with a signature of polygenic adaptation driven primarily by the Sardinian population. Although the polygenic score-based analysis showed a much subtler signature in mainland European populations, we found a clear and robust adaptive signature in the UK population by using a haplotype-based statistic, the trait singleton density score (tSDS), driven by the height-increasing alleles (p = 9.1 × 10-4). In summary, by ascertaining height loci in a distant East Asian population, we further supported the evidence of polygenic adaptation at height-associated loci among the Sardinians. In mainland Europeans, the adaptive signature was detected in haplotype-based analysis but not in polygenic score-based analysis..
60. Saori Sakaue, Jun Hirata, Masahiro Kanai, Ken Suzuki, Masato Akiyama, Chun Lai Too, Thurayya Arayssi, Mohammed Hammoudeh, Samar Al Emadi, Basel K Masri, Hussein Halabi, Humeira Badsha, Imad W Uthman, Richa Saxena, Leonid Padyukov, Makoto Hirata, Koichi Matsuda, Yoshinori Murakami, Yoichiro Kamatani, Yukinori Okada, Dimensionality reduction reveals fine-scale structure in the Japanese population with consequences for polygenic risk prediction., Nature communications, 10.1038/s41467-020-15194-z, 11, 1, 1569-1569, 2020.03, The diversity in our genome is crucial to understanding the demographic history of worldwide populations. However, we have yet to know whether subtle genetic differences within a population can be disentangled, or whether they have an impact on complex traits. Here we apply dimensionality reduction methods (PCA, t-SNE, PCA-t-SNE, UMAP, and PCA-UMAP) to biobank-derived genomic data of a Japanese population (n = 169,719). Dimensionality reduction reveals fine-scale population structure, conspicuously differentiating adjacent insular subpopulations. We further enluciate the demographic landscape of these Japanese subpopulations using population genetics analyses. Finally, we perform phenome-wide polygenic risk score (PRS) analyses on 67 complex traits. Differences in PRS between the deconvoluted subpopulations are not always concordant with those in the observed phenotypes, suggesting that the PRS differences might reflect biases from the uncorrected structure, in a trait-dependent manner. This study suggests that such an uncorrected structure can be a potential pitfall in the clinical application of PRS..
61. Chikashi Terao, Akari Suzuki, Yukihide Momozawa, Masato Akiyama, Kazuyoshi Ishigaki, Kazuhiko Yamamoto, Koichi Matsuda, Yoshinori Murakami, Steven A McCarroll, Michiaki Kubo, Po-Ru Loh, Yoichiro Kamatani, Chromosomal alterations among age-related haematopoietic clones in Japan., Nature, 10.1038/s41586-020-2426-2, 584, 7819, 130-135, 2020.08, The extent to which the biology of oncogenesis and ageing are shaped by factors that distinguish human populations is unknown. Haematopoietic clones with acquired mutations become common with advancing age and can lead to blood cancers1-10. Here we describe shared and population-specific patterns of genomic mutations and clonal selection in haematopoietic cells on the basis of 33,250 autosomal mosaic chromosomal alterations that we detected in 179,417 Japanese participants in the BioBank Japan cohort and compared with analogous data from the UK Biobank. In this long-lived Japanese population, mosaic chromosomal alterations were detected in more than 35.0% (s.e.m., 1.4%) of individuals older than 90 years, which suggests that such clones trend towards inevitability with advancing age. Japanese and European individuals exhibited key differences in the genomic locations of mutations in their respective haematopoietic clones; these differences predicted the relative rates of chronic lymphocytic leukaemia (which is more common among European individuals) and T cell leukaemia (which is more common among Japanese individuals) in these populations. Three different mutational precursors of chronic lymphocytic leukaemia (including trisomy 12, loss of chromosomes 13q and 13q, and copy-neutral loss of heterozygosity) were between two and six times less common among Japanese individuals, which suggests that the Japanese and European populations differ in selective pressures on clones long before the development of clinically apparent chronic lymphocytic leukaemia. Japanese and British populations also exhibited very different rates of clones that arose from B and T cell lineages, which predicted the relative rates of B and T cell cancers in these populations. We identified six previously undescribed loci at which inherited variants predispose to mosaic chromosomal alterations that duplicate or remove the inherited risk alleles, including large-effect rare variants at NBN, MRE11 and CTU2 (odds ratio, 28-91). We suggest that selective pressures on clones are modulated by factors that are specific to human populations. Further genomic characterization of clonal selection and cancer in populations from around the world is therefore warranted..
62. Ayako Okita, Yusuke Murakami, Shotaro Shimokawa, Jun Funatsu, Kohta Fujiwara, Shunji Nakatake, Yoshito Koyanagi, Masato Akiyama, Atsunobu Takeda, Toshio Hisatomi, Yasuhiro Ikeda, Koh-Hei Sonoda, Changes of Serum Inflammatory Molecules and Their Relationships with Visual Function in Retinitis Pigmentosa., Investigative ophthalmology & visual science, 10.1167/iovs.61.11.30, 61, 11, 30-30, 2020.09, Purpose: Retinal degeneration involves neuroinflammation, and pro-inflammatory cytokines/chemokines are markedly increased in the eyes of patients with retinitis pigmentosa (RP). In this study, we investigated the changes of serum cytokines/chemokines in RP, and their relationships with visual parameters. Methods: Forty-five consecutive patients with typical RP aged 20 to -39 years and 28 age-matched and gender-matched controls were included. Fifteen cytokines (interleukin [IL]-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, 1L-15, IL-17, IL-23, interferon [IFN]-γ, and tumor necrosis factor [TNF]-α, TNF-β) and 9 chemokines (eotaxin, growth-related oncogene [GRO]-α, I-309, IL-8, IFN-γ-inducible protein [IP]-10, monocyte chemotactic protein [MCP]-1, MCP-2, regulated activation normal T-cell expressed and secreted [RANTES], and thymus and activated regulated chemokine [TARC]) in the serum were simultaneously measured by a multiplexed immunoarray (Q-Plex). Relationships between these cytokines/chemokines and indices of central vision, such as visual acuity (VA), the values of static perimetry tests (Humphrey Field analyzer, the central 10-2 program), and optical coherence tomography measures were analyzed in the patients with RP. Results: Among the 15 cytokines and 9 chemokines, serum IL-8 and RANTES levels were significantly increased in patients with RP compared with controls (IL-8: P < 0.0001; RANTES: P < 0.0001). Among the elevated cytokines/chemokines, the levels of IL-8 were negatively correlated with VA (ρ = 0.3596 and P = 0.0165), and the average retinal sensitivity of four central points (ρ = -0.3691 and P = 0.0291), and 12 central points (ρ = -0.3491 and P = 0.0398), as well as the central subfield thickness (ρ = -0.3961 and P = 0.0094), and ellipsoid zone width (ρ = -0.3841 and P = 0.0120). Conclusions: Peripheral inflammatory response may be activated and serum IL-8 levels are associated with central vision in patients with RP..
63. Koji M Nishiguchi, Hiroshi Kunikata, Kosuke Fujita, Kazuki Hashimoto, Yoshito Koyanagi, Masato Akiyama, Yasuhiro Ikeda, Yukihide Momozawa, Koh-Hei Sonoda, Akira Murakami, Yuko Wada, Toru Nakazawa, Association of CRX genotypes and retinal phenotypes confounded by variable expressivity and electronegative electroretinogram., Clinical & experimental ophthalmology, 10.1111/ceo.13743, 48, 5, 644-657, 2020.07, IMPORTANCE: A framework for understanding the phenotypic features of CRX retinopathy was established. BACKGROUND: To perform a phenotype-genotype correlation analysis in two groups of patients with heterozygous mutations in distinct locations of the CRX gene, encoding the cone-rod homeobox. DESIGN: Multicentre retrospective study. PARTICIPANTS: Twenty-one Japanese patients from 14 families with a heterozygous CRX mutation. METHODS: Retrospective data analysis. MAIN OUTCOME MEASURES: Clinical records on CRX mutation, symptoms, best-corrected visual acuity (BCVA), visual field, fundus photography, fundus auto-fluorescence, optical coherence tomography and electroretinograms (ERGs). RESULTS: Six different CRX heterozygous mutations were identified in the subjects. Twelve patients from 9 families shared the p.R41W mutation and 1 patient had the p.R43C mutation, both of which affect the homeobox domain of CRX. These patients often displayed adult-onset retinal dystrophy with macular degeneration. In contrast, five patients with downstream mutations (p.S204fs, p.S213fs, p.G243X and p.L299F) displayed retinal degeneration or macular degeneration with bone-spicule pigmentation. Three asymptomatic carriers with different mutations (p.R41W, p.S213fs and p.G243X) were present in both groups. Nearly all patients and carriers had an electronegative ERG in response to a bright flash under dark adaptation. There was no cross-sectional association between patients' age and BCVA, despite progressive decline in BCVA. CONCLUSIONS AND RELEVANCE: Heterozygous mutations within or downstream of the homeobox domain in CRX relate to the difference associated retinal phenotypes, which was confounded by variable expressivity and electronegative ERGs. CRX mutations should be considered in patients with an electronegative ERG with minimal or no macular changes..
64. Koji Miura Nishiguchi, Kosuke Fujita, Yasuhiro Ikeda, Hiroshi Kunikata, Yoshito Koyanagi, Masato Akiyama, Toshiaki Abe, Yuko Wada, Koh-Hei Sonoda, Toru Nakazawa, A founder Alu insertion in RP1 gene in Japanese patients with retinitis pigmentosa., Japanese journal of ophthalmology, 10.1007/s10384-020-00732-5, 64, 4, 346-350, 2020.07, PURPOSE: To screen for the 328 bp Alu insertion (c.4052_4053ins328, p.Tyr1352Alafs) in RP1 in a group of retinitis pigmentosa (RP) patients who had been previously identified with a heterozygous deleterious mutation in the gene. STUDY DESIGN: Prospective, clinical and experimental study. METHODS: The Alu insertion in RP1 was screened with an optimized PCR-based method in 26 RP patients with a heterozygous deleterious mutation (nonsense or frameshift) in RP1 that had been identified in a preceding genetic study. The genetic location of the previously identified mutation and its inheritance pattern were assessed. RESULTS: Out of 26 RP patients with a heterozygous deleterious mutation in RP1, 5 (19.2%) were found to carry an additional heterozygous Alu insertion, presumably resulting in a compound heterozygous state. This included 3 patients who had been previously diagnosed as autosomal dominant RP based on genetic findings. They were re-diagnosed as having an autosomal recessive disease following our new findings. In all patients identified with the Alu insertion, the other mutations found in the preceding study were outside the defined region in exon 4 (encoding amino acids 677 to 917) in which truncation mutations have been suggested to exert a dominant negative effect. CONCLUSION: The founder Alu insertion in RP1 is an important cause of autosomal recessive RP in Japanese patients and can be missed in standard targeted resequencing. Screening optimized for this mutation is warranted, particularly in patients with a heterozygous deleterious mutation outside the defined region in exon 4 of RP1..
65. Jie Zheng, Yuemiao Zhang, Humaira Rasheed, Venexia Walker, Yuka Sugawara, Jiachen Li, Yue Leng, Benjamin Elsworth, Robyn E Wootton, Si Fang, Qian Yang, Stephen Burgess, Philip C Haycock, Maria Carolina Borges, Yoonsu Cho, Rebecca Carnegie, Amy Howell, Jamie Robinson, Laurent F Thomas, Ben Michael Brumpton, Kristian Hveem, Stein Hallan, Nora Franceschini, Andrew P Morris, Anna Köttgen, Cristian Pattaro, Matthias Wuttke, Masayuki Yamamoto, Naoki Kashihara, Masato Akiyama, Masahiro Kanai, Koichi Matsuda, Yoichiro Kamatani, Yukinori Okada, Robin Walters, Iona Y Millwood, Zhengming Chen, George Davey Smith, Sean Barbour, Canqing Yu, Bjørn Olav Åsvold, Hong Zhang, Tom R Gaunt, Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease., International journal of epidemiology, 10.1093/ije/dyab203, 2021.10, BACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included. RESULTS: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD..
66. Yujiro Mori, Mitsuru Arima, Emi Ueda, Kohta Fujiwara, Eiko Seki, Takahito Nakama, Shoko Tsukamoto, Masato Akiyama, Koh-Hei Sonoda, Risk factors for myopia at 1-year corrected age following laser photocoagulation for retinopathy of prematurity., Eye (London, England), 10.1038/s41433-020-01321-z, 35, 10, 2820-2825, 2021.10, BACKGROUND/OBJECTIVES: The prevalence of myopia is higher in preterm infants who underwent laser photocoagulation (LPC) for retinopathy of prematurity (ROP). The aim of this study was to investigate factors associated with myopia in preterm infants who undergo LPC for ROP. SUBJECTS/METHODS: We retrospectively analysed the medical records of preterm infants born at Kyushu University Hospital (October 2008-March 2018) at ≤32 weeks of gestational age or with birth weight ≤1500 g. We evaluated the associations between nine clinical factors and the spherical equivalent at 1-year corrected age by performing multivariable linear regression in LPC-treated ROP patients. RESULTS: Among the 485 infants enroled, 76 developed ROP requiring treatment. Of these, 71 underwent LPC, which was provided to 63 infants as the primary treatment (LPC alone or the combination therapy of LPC and intravitreal injection of bevacizumab [IVB]) and to eight infants as additional LPC after IVB monotherapy. The results of a refractive examination at 1-year corrected age were available for 110 eyes of 56 infants (78.9%). The mean ± standard deviation of the SE value was -0.5 ± 3.0 dioptres (D). Multivariable linear regression analysis revealed a significant association between laser spot count and SE value (ß = -0.081 ± 0.040 D per 100 spots [mean ± standard error], p = 0.045). CONCLUSIONS: Our results suggest that an increased laser spot count observed during ROP treatment associates with myopia..
67. Yoshito Koyanagi, Masato Akiyama, Koji M Nishiguchi, Yukihide Momozawa, Yoichiro Kamatani, Sadaaki Takata, Chihiro Inai, Yusuke Iwasaki, Mikako Kumano, Yusuke Murakami, Shiori Komori, Dan Gao, Kentaro Kurata, Katsuhiro Hosono, Shinji Ueno, Yoshihiro Hotta, Akira Murakami, Hiroko Terasaki, Yuko Wada, Toru Nakazawa, Tatsuro Ishibashi, Yasuhiro Ikeda, Michiaki Kubo, Koh-Hei Sonoda, Regional differences in genes and variants causing retinitis pigmentosa in Japan., Japanese journal of ophthalmology, 10.1007/s10384-021-00824-w, 65, 3, 338-343, 2021.05, PURPOSE: To investigate the regional differences in the genes and variants causing retinitis pigmentosa (RP) in Japan STUDY DESIGN: Retrospective multicenter study METHODS: In total, 1204 probands of each pedigree clinically diagnosed with nonsyndromic RP were enrolled from 5 Japanese facilities. The regions were divided into the Tohoku region, the Kanto and Chubu regions, and the Kyushu region according to the location of the hospitals where the participants were enrolled. We compared the proportions of the causative genes and the distributions of the pathogenic variants among these 3 regions. RESULTS: The proportions of genetically solved cases were 29.4% in the Tohoku region (n = 500), 29.6% in the Kanto and Chubu regions (n = 196), and 29.7% in the Kyushu region (n = 508), which did not differ statistically (P = .99). No significant regional differences in the proportions of each causative gene in genetically solved patients were observed after correction by multiple testing. Among the 29 pathogenic variants detected in all 3 regions, only p.(Pro347Leu) in RHO was an autosomal dominant variant; the remaining 28 variants were found in autosomal recessive genes. Conversely, 78.6% (275/350) of the pathogenic variants were detected only in a single region, and 6 pathogenic variants (p.[Asn3062fs] in EYS, p.[Ala315fs] in EYS, p.[Arg872fs] in RP1, p.[Ala126Val] in RDH12, p.[Arg41Trp] in CRX, and p.[Gly381fs] in PRPF31) were frequently found in ≥ 4 patients in the single region. CONCLUSION: We observed region-specific pathogenic variants in the Japanese population. Further investigations of causative genes in multiple regions in Japan will contribute to the expansion of the catalog of genetic variants causing RP..
68. Shotaro Shimokawa, Yusuke Murakami, Kohta Fujiwara, Jun Funatsu, Shunji Nakatake, Yoshito Koyanagi, Masato Akiyama, Noriko Yoshida, Atsunobu Takeda, Yasuhiro Ikeda, Koh-Hei Sonoda, Recurrence Rate of Cystoid Macular Edema with Topical Dorzolamide Treatment and Its Risk Factors in Retinitis Pigmentosa., Retina (Philadelphia, Pa.), 10.1097/IAE.0000000000003286, 2021.08, PURPOSE: To investigate the rate of the recurrence of cystoid macular edema (CME) secondary to retinitis pigmentosa (RP) after the initiation of topical dorzolamide and the recurrence risk factors. METHODS: We retrospectively analyzed the data of RP patients at Kyushu University Hospital. We included patients who showed a treatment response to 1.0% topical dorzolamide. The day of treatment initiation was set as the baseline. Topical dorzolamide treatment was continued during the follow-up. The recurrence of CME (defined as a >20% increase in central subfield thickness [CST] compared to previous visit, or a CST value that exceed baseline value) was evaluated at each follow-up visit. Risk factors for RP-CME recurrence were analyzed by Cox proportional hazards modeling. A Kaplan-Meier survival analysis was used to evaluate the time to recurrent RP-CME. RESULTS: Forty RP-CME patients showed a treatment response to topical dorzolamide. During the mean 3.9-yr follow-up, 14 patients exhibited recurrence; its rate was 15.6%, 34.7%, and 48.7% at 1, 3, and 5 years, respectively. A high baseline CST was significantly associated with recurrent (HR 1.11, 95%CI: 1.05-1.18, p=0.0004). CONCLUSIONS: The recurrence rate of RP-CME increased with time. A high baseline CST value was a risk factor for recurrent..
69. Masato Akiyama, Multi-omics study for interpretation of genome-wide association study., Journal of human genetics, 10.1038/s10038-020-00842-5, 66, 1, 3-10, 2021.01, Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with complex traits, including a wide variety of diseases. Despite the successful identification of associated loci, interpreting GWAS findings remains challenging and requires other biological resources. Omics, including genomics, transcriptomics, proteomics, metabolomics, and epigenomics, are increasingly used in a broad range of research fields. Integrative analyses applying GWAS with these omics data are expected to expand our knowledge of complex traits and provide insight into the pathogenesis of complex diseases and their causative factors. Recently, associations between genetic variants and omics data have been comprehensively evaluated, providing new information on the influence of genetic variants on omics. Furthermore, recent advances in analytic methods, including single-cell technologies, have revealed previously unknown disease mechanisms. To advance our understanding of complex traits, integrative analysis using GWAS with multi-omics data is needed. In this review, I describe successful examples of integrative analyses based on omics and GWAS, discuss the limitations of current multi-omics analyses, and provide a perspective on future integrative studies..
70. Yusuke Murakami, Yoshito Koyanagi, Masatoshi Fukushima, Marika Yoshimura, Kohta Fujiwara, Masato Akiyama, Yukihide Momozawa, Shinji Ueno, Hiroko Terasaki, Akio Oishi, Manabu Miyata, Hanako Ikeda, Akitaka Tsujikawa, Kei Mizobuchi, Takaaki Hayashi, Kaoru Fujinami, Kazushige Tsunoda, Jun Young Park, Jinu Han, Min Kim, Christopher Seungkyu Lee, Sang Jin Kim, Tae Kwann Park, Kwangsic Joo, Se Joon Woo, Yasuhiro Ikeda, Koh-Hei Sonoda, Genotype and Long-term Clinical Course of Bietti Crystalline Dystrophy in Korean and Japanese Patients., Ophthalmology. Retina, 10.1016/j.oret.2021.02.009, 2021.02, PURPOSE: To investigate the genotype and long-term clinical phenotype of patients with Bietti crystalline dystrophy (BCD) in Korea and Japan. DESIGN: Retrospective case series. PARTICIPANTS: We analyzed 62 patients with clinical features of BCD who harbor pathogenic biallelic CYP4V2 variants in their homozygote or compound heterozygote. METHODS: Data were collected from patient charts, including age, best-corrected visual acuity (BCVA), Goldmann perimetry results, fundus photography, OCT findings, fundus autofluorescence results, and electroretinography findings. We compared the clinical course of the patients with homozygous c.802-8_810de117insGC [exon7del], the most common mutation in the East Asian population, with those of the patients with other genotypes. MAIN OUTCOME MEASURES: Best-corrected visual acuity, visual field (VF), and their changes during follow-up. RESULTS: The mean age at the first visit was 55.2 years, with a mean follow-up of 7.1 years. The mean BCVAs at the first and last visits were 0.28 logarithm of the minimum angle of resolution (logMAR) and 0.89 logMAR, respectively. In genetic testing, c.802-8_810de117insGC was detected in 86 of 124 alleles of the patients, and 36 patients were homozygous for this mutation. The age, BCVA, VF area, central foveal thickness, and abnormal hypoautofluorescent area at either the first or last visit were not different between the exon7del homozygotes and the others. The mean BCVA changes per year were 0.089 logMAR in the exon7del homozygotes and 0.089 logMAR in the others. An age- and gender-adjusted linear regression analysis showed no association between the exon7del homozygote status and the rate of vision loss. Characteristic crystalline deposits in the posterior pole were generally observed in younger patients and disappeared over time along with progressive retinochoroidal atrophy. CONCLUSIONS: Patients with BCD and a homozygote for c.802-8_810de117insGC accounted for more than 50% of this cohort of Korean and Japanese patients, and the clinical effect of this deleterious variant was not severe in the spectrum of CYP4V2 retinopathy..
71. Puya Gharahkhani, Eric Jorgenson, Pirro Hysi, Anthony P Khawaja, Sarah Pendergrass, Xikun Han, Jue Sheng Ong, Alex W Hewitt, Ayellet V Segrè, John M Rouhana, Andrew R Hamel, Robert P Igo Jr, Helene Choquet, Ayub Qassim, Navya S Josyula, Jessica N Cooke Bailey, Pieter W M Bonnemaijer, Adriana Iglesias, Owen M Siggs, Terri L Young, Veronique Vitart, Alberta A H J Thiadens, Juha Karjalainen, Steffen Uebe, Ronald B Melles, K Saidas Nair, Robert Luben, Mark Simcoe, Nishani Amersinghe, Angela J Cree, Rene Hohn, Alicia Poplawski, Li Jia Chen, Shi-Song Rong, Tin Aung, Eranga Nishanthie Vithana, Gen Tamiya, Yukihiro Shiga, Masayuki Yamamoto, Toru Nakazawa, Hannah Currant, Ewan Birney, Xin Wang, Adam Auton, Michelle K Lupton, Nicholas G Martin, Adeyinka Ashaye, Olusola Olawoye, Susan E Williams, Stephen Akafo, Michele Ramsay, Kazuki Hashimoto, Yoichiro Kamatani, Masato Akiyama, Yukihide Momozawa, Paul J Foster, Peng T Khaw, James E Morgan, Nicholas G Strouthidis, Peter Kraft, Jae H Kang, Chi Pui Pang, Francesca Pasutto, Paul Mitchell, Andrew J Lotery, Aarno Palotie, Cornelia van Duijn, Jonathan L Haines, Chris Hammond, Louis R Pasquale, Caroline C W Klaver, Michael Hauser, Chiea Chuen Khor, David A Mackey, Michiaki Kubo, Ching-Yu Cheng, Jamie E Craig, Stuart MacGregor, Janey L Wiggs, Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries., Nature communications, 10.1038/s41467-020-20851-4, 12, 1, 1258-1258, 2021.02, Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates..
72. Keijiro Ishikawa, Masato Akiyama, Kenichiro Mori, Takahito Nakama, Shoji Notomi, Shintaro Nakao, Ri-Ichiro Kohno, Atsunobu Takeda, Koh-Hei Sonoda, Drainage retinotomy confers risk of epiretinal membrane formation following vitrectomy for rhegmatogenous retinal detachment repair., American journal of ophthalmology, 10.1016/j.ajo.2021.07.028, 2021.07, PURPOSE: To describe the factors associated with epiretinal membrane (ERM) formation in eyes treated with pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD). DESIGN: Nation-wide, multi-center, clinical cohort study based on registry data. METHODS: Subjects: The 2239 cases treated with PPV for RRD repair registered in the Japan-Retinal Detachment Registry between February 2016 and March 2017. PROCEDURES: Associations of 13 baseline characteristics and eight surgical procedures with ERM formation were evaluated using univariate analysis. We conducted a propensity score-matched analysis for the significantly associated clinical factor(s). MAIN OUTCOME MEASURES: ERM formation after six months of vitrectomy. RESULTS: ERM had developed in 104 cases (4.6%) by six months. We found that a drainage retinotomy was significantly associated with ERM after multiple testing correction (odds ratio [OR] = 2.22, 95% confidence interval [CI] = 1.50-3.31, P < 0.001). In the propensity score-matched analysis (N = 492 in each group), we confirmed a significant difference in the incidence of ERM after six months of vitrectomy (8.3% and 2.6% in cases with and without drainage retinotomy, respectively; OR = 3.35, 95% CI 1.77-6.33; P < 0.001). CONCLUSIONS: Eyes treated with PPV combined with drainage retinotomy are more likely to develop ERM postoperatively..
73. Mitsuru Arima, Shintaro Nakao, Yoshihiro Kaizu, Iori Wada, Muneo Yamaguchi, Kohta Fujiwara, Masato Akiyama, Alan W Stitt, Koh-Hei Sonoda, Diabetic vascular hyperpermeability: optical coherence tomography angiography and functional loss assessments of relationships among retinal vasculature changes., Scientific reports, 10.1038/s41598-021-83334-6, 11, 1, 4185-4185, 2021.02, Our study assessed the influence of vascular permeability on vascular flow density (FD)-correlated retinal sensitivity (RS) in DR. In this cross-sectional, prospective, consecutive study, RS in the extrafoveal macula of DR patient was measured by microperimetry. FD was measured in the total, superficial, and deep capillary plexus layers (TCP, SCP, and DCP) by optical coherence tomography angiography. All measurement points were classified into four categories according to intensity of fluorescein leakage and FD, and the RS reduction was compared. A stratified analysis by retinal thickness (RT) was also performed. Fourteen eyes (14 patients) were enrolled. FDs at 207 RS measurement points were analyzable. For TCP, SCP and DCP, the leakage did not decrease RS at points where FD was maintained. The greater the leakage, the smaller the RS reduction at points with low FD in TCP (P = .020). Points with high leakage showed a significant smaller RS reduction than points with low leakage (P = .001 for TCP, P = .040 for SCP, and P = .046 for DCP) only in areas with low RT and low FD. Our results suggested that vascular hyperpermeability may inhibit the RS reduction in the non-edematous ischemic diabetic retina..
74. Mariko Sasaki, Masahiro Miyake, Kohta Fujiwara, Hiroyuki Nanba, Masato Akiyama, Yasuo Yanagi, Sei Harada, Yasuharu Tabara, Miho Yasuda, Hidetoshi Yamashita, Takamasa Kayama, Kazuo Tsubota, Fumihiko Matsuda, Sawako Hashimoto, Emi Ueda, Toshiharu Ninomiya, Toru Takebayashi, Akitaka Tsujikawa, Koh-Hei Sonoda, Ryo Kawasaki, Cohort Profile: The Ganka-Ekigaku Network (GEN), a Network of Japanese Ophthalmological Epidemiology Studies., Ophthalmic epidemiology, 10.1080/09286586.2020.1815803, 28, 3, 237-243, 2021.06, PURPOSE: Japan has been known as a super-aged society, and ageing is a well-known risk factor for blinding eye diseases. However, epidemiological studies in ophthalmology are still scarce in Japan, and the sizes of the cohorts are relatively small. "Ganka-Ekigaku Network" (GEN, an acronym for the epidemiological network in ophthalmology in Japanese) is established to develop a capacity to boost each epidemiological study and enrich a potential inter-study collaboration to identify risk factors of visual impairment in aged society. METHODS: We reviewed cohort studies in Japan with the inclusion criteria as: (1) at least n = 1000 at baseline, (2) multiple modalities of ophthalmic data, and (3) diagnosis reviewed by ophthalmologist(s), and (4) ophthalmologists are involved in the investigators group. As of January 2020, GEN includes 4 individual Japanese epidemiological studies namely, Hisayama study, Yamagata Study (Funagata), Tsuruoka Metabolomics Cohort study, and the Nagahama Prospective Genome Cohort for Comprehensive Human Bioscience. RESULTS: GEN includes approximately 25,000 Japanese participants. The baseline surveys started from 1998 to 2012, and since then the data has been prospectively collected approximately every 5 years. A variety of ophthalmic measurements and other factors have been collected in each study in GEN: ophthalmic measurements (fundus photography, optical coherence tomography, etc.), systemic conditions (laboratory data, etc.), and others (DNA, etc.). CONCLUSION: GEN is an open platform for observational ophthalmic epidemiological studies to share standardized methodologies. While each study in GEN pursues specific and original research questions, standardization of the methods will enable us to conduct reliable meta-analysis/pooled data analyses..
75. Koji M Nishiguchi, Fuyuki Miya, Yuka Mori, Kosuke Fujita, Masato Akiyama, Takashi Kamatani, Yoshito Koyanagi, Kota Sato, Toru Takigawa, Shinji Ueno, Misato Tsugita, Hiroshi Kunikata, Katarina Cisarova, Jo Nishino, Akira Murakami, Toshiaki Abe, Yukihide Momozawa, Hiroko Terasaki, Yuko Wada, Koh-Hei Sonoda, Carlo Rivolta, Tatsuhiko Tsunoda, Motokazu Tsujikawa, Yasuhiro Ikeda, Toru Nakazawa, A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa., Communications biology, 10.1038/s42003-021-01662-9, 4, 1, 140-140, 2021.01, The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P < 5.0 × 10-8, all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a non-synonymous variant (c.2528 G > A, p.G843E) of unknown significance. mRNA harboring c.2528 G > A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528 G > A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666 A > T, p.S2556C), possibly representing an unreported disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare monogenic disorder and identified a high frequency variant potentially linked to development of local genome therapeutics..
76. Saori Sakaue, Masahiro Kanai, Yosuke Tanigawa, Juha Karjalainen, Mitja Kurki, Seizo Koshiba, Akira Narita, Takahiro Konuma, Kenichi Yamamoto, Masato Akiyama, Kazuyoshi Ishigaki, Akari Suzuki, Ken Suzuki, Wataru Obara, Ken Yamaji, Kazuhisa Takahashi, Satoshi Asai, Yasuo Takahashi, Takao Suzuki, Nobuaki Shinozaki, Hiroki Yamaguchi, Shiro Minami, Shigeo Murayama, Kozo Yoshimori, Satoshi Nagayama, Daisuke Obata, Masahiko Higashiyama, Akihide Masumoto, Yukihiro Koretsune, Kaoru Ito, Chikashi Terao, Toshimasa Yamauchi, Issei Komuro, Takashi Kadowaki, Gen Tamiya, Masayuki Yamamoto, Yusuke Nakamura, Michiaki Kubo, Yoshinori Murakami, Kazuhiko Yamamoto, Yoichiro Kamatani, Aarno Palotie, Manuel A Rivas, Mark J Daly, Koichi Matsuda, Yukinori Okada, A cross-population atlas of genetic associations for 220 human phenotypes., Nature genetics, 10.1038/s41588-021-00931-x, 53, 10, 1415-1424, 2021.10, Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (ntotal = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics..
77. Akiyama M, Ishigaki K, Sakaue S, Momozawa Y, Horikoshi M, Hirata M, Matsuda K, Ikegawa S, Takahashi A, Kanai M, Suzuki S, Matsui D, Naito M, Yamaji T, Iwasaki M, Sawada N, Tanno K, Sasaki M, Hozawa A, Minegishi N, Wakai K, Tsugane S, Shimizu A, Yamamoto M, Okada Y, Murakami Y, Kubo M, Kamatani Y, Characterizing rare and low-frequency height-associated variants in the Japanese population., Nature Communications, 10.1038/s41467-019-12276-5, 10, 4393, 2019.10, [URL].
78. Kanai M, Akiyama M, Takahashi A, Matoba N, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M, Matsuda K, Kubo M, Okada Y, Kamatani Y, Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases, Nature Genetics, 10.1038/s41588-018-0047-6, 50, 3, 390-400, 2018.03.
79. Suzuki K, Akiyama M, Ishigaki K, Kanai M, Hosoe J, Shojima N, Hozawa A, Kadota A, Kuriki K, Naito M, Tanno K, Ishigaki Y, Hirata M, Matsuda K, Iwata N, Ikeda M, Sawada N, Yamaji T, Iwasaki M, Ikegawa S, Maeda S, Murakami Y, Wakai K, Tsugane S, Sasaki M, Yamamoto M, Okada Y, Kubo M, Kamatani Y, Horikoshi M, Yamauchi T, Kadowaki T., Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population, Nature Genetics, 10.1038/s41588-018-0332-4, 51, 3, 379-386, 2019.03.
80. Ishigaki K, Akiyama M, Kanai M, Takahashi A, Kawakami E, Sugishita H, Sakaue S, Matoba N, Low SK, Okada Y, Terao C, Amariuta T, Gazal S, Kochi Y, Horikoshi M, Suzuki K, Ito K, Koyama S, Ozaki K, Niida S, Sakata Y, Sakata Y, Kohno T, Shiraishi K, Momozawa Y, Hirata M, Matsuda K, Ikeda M, Iwata N, Ikegawa S, Kou I, Tanaka T, Nakagawa H, Suzuki A, Hirota T, Tamari M, Chayama K, Miki D, Mori M, Nagayama S, Daigo Y, Miki Y, Katagiri T, Ogawa O, Obara W, Ito H, Yoshida T, Imoto I, Takahashi T, Tanikawa C, Suzuki T, Sinozaki N, Minami S, Yamaguchi H, Asai S, Takahashi Y, Yamaji K, Takahashi K, Fujioka T, Takata R, Yanai H, Masumoto A, Koretsune Y, Kutsumi H, Higashiyama M, Murayama S, Minegishi N, Suzuki K, Tanno K, Shimizu A, Yamaji T, Iwasaki M, Sawada N, Uemura H, Tanaka K, Naito M, Sasaki M, Wakai K, Tsugane S, Yamamoto M, Yamamoto K, Murakami Y, Nakamura Y, Raychaudhuri S, Inazawa J, Yamauchi T, Kadowaki T, Kubo M, Kamatani Y., Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases, Nature Genetics, 10.1038/s41588-020-0640-3, 52, 7, 669-679, 2020.07.
81. Takeuchi F*, Akiyama M*, Matoba N*, Katsuya T*, Nakatochi M*, Tabara Y*, Narita A, Saw WY, Moon S, Spracklen CN, Chai JF, Kim YJ, Zhang L, Wang C, Li H, Li H, Wu JY, Dorajoo R, Nierenberg JL, Wang YX, He J, Bennett DA, Takahashi A, Momozawa Y, Hirata M, Matsuda K, Rakugi H, Nakashima E, Isono M, Shirota M, Hozawa A, Ichihara S, Matsubara T, Yamamoto K, Kohara K, Igase M, Han S, Gordon-Larsen P, Huang W, Lee NR, Adair SL, Hwang MY, Lee J, Chee ML, Sabanayagam C, Zhao W, Shi Y, Liu J, Reilly DF, Sun L, Huo S, Edwards T, Long J, Chang LC, Chen CH, Yuan JM, Koh WP, Friedlander Y, Kelly TN, Wei WB, Xu L, Cai H, Xiang YB, Lin K, Clarke R, Walters RG, Millwood IY, Li L, Chambers JC, Kooner JS, Elliott P, van der Harst P, The International Genomics of Blood Pressure (iGEN-BP) Consortium, Chen Z, Sasaki M, Shu XO, Jonas JB, He J, Heng CK, Chen YT, Zheng W, Lin X, Teo YY, Tai ES, Cheng CY, Wong TY, Sim X, Mohlke KL, Yamamoto M, Kim BJ, Miki T, Nabika T, Yokota M, Kamatani Y, Kubo M, Kato N., Interethnic analyses of blood pressure loci in populations of East Asian and European descent, Nature Communications, 10.1038/s41467-018-07345-0, 9, 2018.11.
82. Noguchi E*, Akiyama M*, Yagami A*, Hirota T, Okada T, Kato Z, Kishikawa R, Fukutomi Y, Hide M, Morita E, Aihara M, Hiragun M, Chinuki Y, Okabe T, Ito A, Adachi A, Fukunaga A, Kubota Y, Aoki T, Aoki Y, Nishioka K, Adachi T, Kanazawa N, Miyazawa H, Sakai H, Miyazawa H, Sakai H, Kozuka T, Kitamura H, Hashizume H, Kanegane C, Matsuda K, Sugiyama K, Tokuda R, Furuta J, Higashimoto I, Kato A, Seishima M, Taijiri A, Tomura A, Taniguchi H, Kojima H, Tanaka H, Sakai BA, Morii W, Nakamura M, Kamatani Y, Takahashi A, Kubo M, Tamari M, Saito H, Matsunaga K, HLA-DQ and RBFOX1 as susceptibility genes for an outbreak of hydrolyzed wheat allergy, Journal of Allergy and Clinical Immunology, 10.1016/j.jaci.2019.06.034, 144, 5, 1354-1363, 2019.11.
83. Matoba N, Akiyama M, Ishigaki K, Kanai M, Takahashi A, Momozawa Y, Ikegawa S, Ikeda M, Iwata N, Hirata M, Matsuda K, Kubo M, Okada Y, Kamatani Y., GWAS of smoking behaviour in 165,436 Japanese people reveals seven new loci and shared genetic architecture, Nature Human Behaviour, 10.1038/s41562-019-0557-y, 3, 5, 471-477, 2019.05.
84. Matoba N, Akiyama M, Ishigaki K, Kanai M, Takahashi A, Momozawa Y, Ikegawa S, Ikeda M, Iwata N, Hirata M, Matsuda K, Murakami Y, Kubo M, Kamatani Y, Okada Y, GWAS of 165,084 Japanese individuals identified nine loci associated with dietary habits., Nature Human Behaviour, 10.1038/s41562-019-0805-1, 4, 3, 308-316, 2020.03.
85. Horikoshi M, Day F, Akiyama M, Hirata M, Kamatani Y, Matsuda K, Ishigaki K, Kanai M, Wright H, Toro CA, Ojeda SR, Lominiczi A, Kubo M, Ong KK, Perry JRB, Elucidating the genetic architecture of reproductive ageing in the Japanese population, Nature Communications, 10.1038/s41467-018-04398-z, 9, 2018.05.
86. Sakaue S, Kanai M, Karjalainen J, Akiyama M, Kurki M, Matoba N, Takahashi A, Hirata M, Kubo M, Matsuda K, Murakami Y; FinnGen, Daly MJ, Kamatani Y, Okada Y., Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan, Nature Medicine, 10.1038/s41591-020-0785-8, 26, 4, 542-548, 2020.04.
87. Zheng Y, Huang T, Wang T, Mei Z, Sun Z, Zhang T, Ellervik C, Chai JF, Sim X, van Dam RM, Tai ES, Koh WP, Dorajoo R, Saw SM, Sabanayagam C, Wong TY, Gupta P, Rossing P, Ahluwalia TS, Vinding RK, Bisgaard H, Bønnelykke K, Wang Y, Graff M, Voortman T, van Rooij FJA, Hofman A, van Heemst D, Noordam R, Estampador AC, Varga TV, Enzenbach C, Scholz M, Thiery J, Burkhardt R, Orho-Melander M, Schulz CA, Ericson U, Sonestedt E, Kubo M, Akiyama M, Zhou A, Kilpeläinen TO, Hansen T, Kleber ME, Delgado G, McCarthy M, Lemaitre RN, Felix JF, Jaddoe VWV, Wu Y, Mohlke KL, Lehtimäki T, Wang CA, Pennell CE, Schunkert H, Kessler T, Zeng L, Willenborg C, Peters A, Lieb W, Grote V, Rzehak P, Koletzko B, Erdmann J, Munz M, Wu T, He M, Yu C, Lecoeur C, Froguel P, Corella D, Moreno LA, Lai CQ, Pitkänen N, Boreham CA, Ridker PM, Rosendaal FR, de Mutsert R, Power C, Paternoster L, Sørensen TIA, Tjønneland A, Overvad K, Djousse L, Rivadeneira F, Lee NR, Raitakari OT, Kähönen M, Viikari J, Langhendries JP, Escribano J, Verduci E, Dedoussis G, König I, Balkau B, Coltell O, Dallongeville J, Meirhaeghe A, Amouyel P, Gottrand F, Pahkala K, Niinikoski H, Hyppönen E, März W, Mackey DA, Gruszfeld D, Tucker KL, Fumeron F, Estruch R, Ordovas JM, Arnett DK, Mook-Kanamori DO, Mozaffarian D, Psaty BM, North KE, Chasman DI, Qi L, Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood, Eur J. Epidemiol, 35, 7, 685-697, 2020.07.
88. Koyanagi Y, Ueno S, Kominami T, Komori S, Akiyama M, Murakami Y, Ikeda Y, Sonoda KH, Terasaki H., Relationship Between Macular Curvature and Common Causative Genes of Retinitis Pigmentosa in Japanese Patients, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 10.1167/iovs.61.10.6, 61, 10, 2020.08.
89. Chen MH, Raffield LM, Mousas A, Sakaue S, Huffman JE, Moscati A, Trivedi B, Jiang T, Akbari P, Vuckovic D, Bao EL, Zhong X, Manansala R, Laplante V, Chen M, Lo KS, Qian H, Lareau CA, Beaudoin M, Hunt KA, Akiyama M, Bartz TM, Ben-Shlomo Y, Beswick A, Bork-Jensen J, Bottinger EP, Brody JA, van Rooij FJA, Chitrala K, Cho K, Choquet H, Correa A, Danesh J, Di Angelantonio E, Dimou N, Ding J, Elliott P, Esko T, Evans MK, Floyd JS, Broer L, Grarup N, Guo MH, Greinacher A, Haessler J, Hansen T, Howson JMM, Huang QQ, Huang W, Jorgenson E, Kacprowski T, Kähönen M, Kamatani Y, Kanai M, Karthikeyan S, Koskeridis F, Lange LA, Lehtimäki T, Lerch MM, Linneberg A, Liu Y, Lyytikäinen LP, Manichaikul A, Martin HC, Matsuda K, Mohlke KL, Mononen N, Murakami Y, Nadkarni GN, Nauck M, Nikus K, Ouwehand WH, Pankratz N, Pedersen O, Preuss M, Psaty BM, Raitakari OT, Roberts DJ, Rich SS, Rodriguez BAT, Rosen JD, Rotter JI, Schubert P, Spracklen CN, Surendran P, Tang H, Tardif JC, Trembath RC, Ghanbari M, Völker U, Völzke H, Watkins NA, Zonderman AB, VA Million Veteran Program, Wilson PWF, Li Y, Butterworth AS, Gauchat JF, Chiang CWK, Li B, Loos RJF, Astle WJ, Evangelou E, van Heel DA, Sankaran VG, Okada Y, Soranzo N, Johnson AD, Reiner AP, Auer PL, Lettre G, Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations, Cell, 182, 5, 1189-1213, 2020.09.
90. Vuckovic D, Bao EL, Akbari P, Lareau CA, Mousas A, Jiang T, Chen M, Raffield LM, Tardaguila M, Huffman JE, Ritchie SC, Megy K, Ponstingl H, Penkett CJ, Albers PK, Wigdor EM, Sakaue S, Moscati A, Manansala R, Lo KS, Qian H, Akiyama M, Bartz TM, Ben-Shlomo Y, Beswick A, Bork-Jensen J, Bottinger EP, Brody JA, van Rooij FJ, Chitrala KN, Cho K, Choquet H, Danesh J, Di Angelantonio E, Dimou N, Ding J, Elliott P, Esko T, Evans MK, Felix SB, Floyd JS, Broer L, Grarup N, Guo M, Greinacher A, Haessler J, Hansen T, Howson J, Huang W, Jorgenson E, Kacprowski T, Kähönen M, Kamatani Y, Kanai M, Karthikeyan S, Koskeridis F, Lange LA, Lehtimäki T, Linneberg A, Liu Y, Lyytikäinen L, Manichaikul A, Matsuda K, Mohlke KL, Mononen N, Murakami Y, Nadkarni G, Nikus K, Pankratz N, Pedersen O, Preuss M, Psaty BM, Raitakari OT, Rich SS, Rodriguez BA, Rosen JD, Rotter JI, Schubert P, Spracklen CN, Surendran P, Tang H, Tardif J, Ghanbari M, Völker U, Völzke H, Watkins NA, Weiss S, VA Million Veteran Program, Cai N, Kundu K, Watt S, Walter K, Zonderman AB, Wilson PW, Li Y, Loos RJ, Knight JC, Georges M, Stegle O, Evangelou E, Okada Y, Roberts DJ, Inouye M, Johnson AD, Auer PL, Astle WJ, Reiner AP, Butterworth AS, Ouwehand WH, Lettre G, Sankaran VG, Soranzo N, The Polygenic and Monogenic Basis of Blood Traits and Diseases, Cell, 182, 5, 1214-1231, 2020.09.
91. Nishiguchi KM, Kunikata H, Fujita K, Hashimoto K, Koyanagi Y, Akiyama M, Ikeda Y, Momozawa Y, Sonoda KH, Murakami A, Wada Y, Nakazawa T., Association of CRX genotypes and retinal phenotypes confounded by variable expressivity and electronegative electroretinogram, Clinical and Experimental Ophthalmology, 10.1111/ceo.13743, 2020.01.
92. Lin Y, Nakatochi M, Hosono Y, Ito H, Kamatani Y, Inoko A, Sakamoto H, Kinoshita F, Kobayashi Y, Ishii H, Ozaka M, Sasaki T, Matsuyama M, Sasahira N, Morimoto M, Kobayashi S, Fukushima T, Ueno M, Ohkawa S, Egawa N, Kuruma S, Mori M, Nakao H, Adachi Y, Okuda M, Osaki T, Kamiya S, Wang C, Hara K, Shimizu Y, Miyamoto T, Hayashi Y, Ebi H, Kohmoto T, Imoto I, Kasugai Y, Murakami Y, Akiyama M, Ishigaki K, Matsuda K, Hirata M, Shimada K, Okusaka T, Kawaguchi T, Takahashi M, Watanabe Y, Kuriki K, Kadota A, Okada R, Mikami H, Takezaki T, Suzuki S, Yamaji T, Iwasaki M, Sawada N, Goto A, Kinoshita K, Fuse N, Katsuoka F, Shimizu A, Nishizuka SS, Tanno K, Suzuki K, Okada Y, Horikoshi M, Yamauchi T, Kadowaki T, Yu H, Zhong J, Amundadottir LT, Doki Y, Ishii H, Eguchi H, Bogumil D, Haiman CA, Marchand LL, Mori M, Risch H, Setiawan VW, Tsugane S, Wakai K, Yoshida T, Matsuda F, Kubo M, Kikuchi S, Matsuo K, Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer, NATURE COMMUNICATIONS, 10.1038/s41467-020-16711-w, 11, 1, 2020.06.
93. Spracklen CN, Horikoshi M, Kim YJ, Lin K, Bragg F, Moon S, Suzuki K, Tam CHT, Tabara Y, Kwak SH, Takeuchi F, Long J, Lim VJY, Chai JF, Chen CH, Nakatochi M, Yao J, Choi HS, Iyengar AK, Perrin HJ, Brotman SM, van de Bunt M, Gloyn AL, Below JE, Boehnke M, Bowden DW, Chambers JC, Mahajan A, McCarthy MI, Ng MCY, Petty JE, Zhang W, Morris AP, Adair LS, Akiyama M, Bian Z, Chan JCN, Chang LC, Chee ML, Chen YI, Chen YT, Chen Z, Chuang LM, Du S, Gordon-Larsen P, Gross M, Guo X, Guo Y, Han S, Howard AG, Huang W, Hung YJ, Hwang MY, Hwu CM, Ichihara S, Isono M, Jang HM, Jiang G, Jonas JB, Kamatani Y, Katsuya T, Kawaguchi T, Khor CC, Kohara K, Lee MS, Lee NR, Li L, Liu J, Luk AO, Lv J, Okada Y, Pereira MA, Sabanayagam C, Shi J, Shin DM, So WY, Takahashi A, Tomlinson B, Tsai FJ, van Dam RM, Xiang YB, Yamamoto K, Yamauchi T, Yoon K, Yu C, Yuan JM, Zhang L, Zheng W, Igase M, Cho YS, Rotter JI, Wang YX, Sheu WHH, Yokota M, Wu JY, Cheng CY, Wong TY, Shu XO, Kato N, Park KS, Tai ES, Matsuda F, Koh WP, Ma RCW, Maeda S, Millwood IY, Lee J, Kadowaki T, Walters RG, Kim BJ, Mohlke KL, Sim X., Identification of type 2 diabetes loci in 433,540 East Asian individuals., Nature, 582, 240-245, 2020.05.
94. Matsunaga H, Ito K, Akiyama M, Takahashi A, Koyama S, Nomura S, Ieki H, Ozaki K, Onouchi Y, Sakaue S, Suna S, Ogishima S, Yamamoto M, Hozawa A, Satoh M, Sasaki M, Yamaji T, Sawada N, Iwasaki M, Tsugane S, Tanaka K, Arisawa K, Ikezaki H, Takashima N, Naito M, Wakai K, Sakata Y, Morita H, Sakata Y, Matsuda K, Murakami Y, Akazawa H, Kubo M, Kamatani Y, Komuro I. , Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease, CIRCULATION-GENOMIC AND PRECISION MEDICINE, 10.1161/CIRCGEN.119.002670, 13, 3, 128-138, 2020.06.
95. Masato Akiyama, Yasuhiro Ikeda, Noriko Yoshida, Shoji Notomi, Yusuke Murakami, Toshio Hisatomi, Hiroshi Enaida, Tatsuro Ishibashi, Therapeutic efficacy of topical unoprostone isopropyl in retinitis pigmentosa, Acta Ophthalmologica, 10.1111/aos.12293, 92, 3, e229-e234, 2014.05, Purpose To evaluate the therapeutic effect of topical unoprostone isopropyl (unoprostone) on patients with retinitis pigmentosa (RP). Methods Forty patients with typical forms of RP were included in the study. Seventeen of 40 patients were treated with 0.12% topical unoprostone twice daily in a randomly selected eye. Patients underwent follow-up examinations every 3 months after treatment. The efficacy of the treatment was monitored by visual acuity and visual field measurement testing using the Humphrey Field Analyzer (HFA: the central 10-2 programme). Moreover, 12 RP patients who were included this study and 12 normal subjects were evaluated in terms of their macular blood flow of both eyes after instillation of unoprostone using the laser speckle method. Results One year after treatment, the 'macular sensitivity', calculated by HFA as the average sensitivity of the central 12 points, was preserved in the fellow eyes as well as the unoprostone-treated eyes. On the other hand, that in the eyes of the control RP patient was significantly decreased. Moreover, there were significantly greater improvements of the 'macular sensitivity' in the unoprostone-treated eyes than the fellow eyes. The change ratios of macular blood flow obtained from both RP patients and normal subjects were significantly increased in both the treated and the fellow eyes. No severe side-effects were observed. Conclusions These results demonstrate that topical unoprostone might have a therapeutic efficacy in patients with RP as a consequence of the macular blood flow improvement as well as its direct neuroprotective effect..
96. Yusuke Murakami, Yasuhiro Ikeda, Masato Akiyama, Kota Fujiwara, Noriko Yoshida, Shunji Nakatake, Shoji Notomi, Takahiro Nabeshima, Toshio Hisatomi, Hiroshi Enaida, Tatsuro Ishibashi, Correlation between macular blood flow and central visual sensitivity in retinitis pigmentosa, Acta Ophthalmologica, 10.1111/aos.12693, 93, 8, e644-e648, 2015.12, Purpose To investigate the changes in macular blood flow and the correlation between those changes and central visual function in patients with retinitis pigmentosa (RP). Methods The mean blur rate (MBR), a quantitative blurring index of the laser speckle pattern that represents retinal and choroidal blood flow, was measured by laser speckle flowgraphy. Mean blur rate values in the macular area were compared between 70 patients with RP and 28 control subjects. The relationships between MBR on the one hand and, on the other, visual acuity (VA), mean deviation (MD) and averaged macular sensitivity of static perimetry tests (Humphrey Filed Analyzer, the central 10-2 program) were analysed in patients with RP. Results Macular MBR was decreased to 75% in patients with RP compared with control subjects (p < 0.0001, Student's t-test). Spearman's rank testing showed that macular MBR was significantly correlated with VA (r = -0.261, p = 0.0299), MD values (r = 0.438, p = 0.0002) and averaged macular sensitivity at the central 4 and 12 points of static perimetry tests (r = 0.426 and 0.442, p = 0.0003 and 0.0002, respectively). Multivariable-adjusted analysis confirmed that MBR was independently associated with MD (p = 0.0002) and macular sensitivity at the central 4 and 12 points (p < 0.0001 and 0.0002, respectively). Conclusions Decreased macular blood flow was associated with reduced macular visual sensitivity in patients with RP. Although the cause-effect relationships remain to be elucidated, these findings suggest that vascular defects may be involved in the pathogenesis of RP such as central vision loss..
97. Yukinori Okada, Akari Suzuki, Katsunori Ikari, Chikashi Terao, Yuta Kochi, Koichiro Ohmura, Koichiro Higasa, Masato Akiyama, Kyota Ashikawa, Masahiro Kanai, Jun Hirata, Naomasa Suita, Yik Ying Teo, Huji Xu, Sang Cheol Bae, Atsushi Takahashi, Yukihide Momozawa, Koichi Matsuda, Shigeki Momohara, Atsuo Taniguchi, Ryo Yamada, Tsuneyo Mimori, Michiaki Kubo, Matthew A. Brown, Soumya Raychaudhuri, Fumihiko Matsuda, Hisashi Yamanaka, Yoichiro Kamatani, Kazuhiko Yamamoto, Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis, American journal of human genetics, 10.1016/j.ajhg.2016.06.019, 99, 2, 366-374, 2016.08, Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10−9), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping..
98. Momozawa Y*, Akiyama M*, Kamatani Y, Arakawa S, Yasuda M, Yoshida S, Oshima T, Mori R, Tanaka K, Mori K, Inoue S, Terasaki H, Yasuma T, Honda S, Miki A, Inoue M, Fujisawa K, Takahashi K, Yasukawa T, Yanagi Y, Kadonosono K, Sonoda KH, Ishibashi T, Takahashi A, Kubo M, Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population, Human Molecular Genetics, 10.1093/hmg/ddw335, 25, 22, 5027-5034, 2016.11.
99. Paisan Ruamviboonsuk, Mongkol Tadarati, Panisa Singhanetr, Sukanya Wattanapokayakit, Punna Kunhapan, Thanyapat Wanitchanon, Nuanjun Wichukchinda, Taisei Mushiroda, Masato Akiyama, Yukihide Momozawa, Michiaki Kubo, Surakameth Mahasirimongkol, Genome-wide association study of neovascular age-related macular degeneration in the Thai population, Journal of Human Genetics, 10.1038/jhg.2017.72, 62, 11, 957-962, 2017.11, We performed a genome-wide association study on 377 cases of neovascular age-related macular degeneration (AMD) and 1074 controls to determine the association of previously reported genetic variants associated with neovascular AMD in the Thai population. All patients were of Thai ancestry. We confirmed the association of age-related maculopathy susceptibility 2 (ARMS2) rs10490924 (P=7.38 × 10'17), HTRA1 rs11200638 (P=5.47 × 10 '17) and complement factor H gene (CFH) rs800292 (P=2.53 × 10 '8) with neovascular AMD, all loci passing the genome-wide significance level (P<5.22 × 10 '8). We also found association of the previously reported CFH rs10737680 (P=1.76 × 10 '6) locus in the discovery sample. Two loci not previously reported to be associated with neovascular AMD were selected for replication in 222 cases and 623 controls. The loci included LINCO1317 rs6733379 and rs2384550 on chromosome 12. LINCO1317 rs6733379 (P=3.85 × 10 '2) remained significantly associated with neovascular AMD after replication. In conclusion, we confirm that ARMS2, HTRA1 and CFH variants are associated with neovascular AMD in the Thai population. Findings from this study also suggest that variants contributing to the susceptibility of neovascular AMD in the Thai population are mostly similar to other Asians with additional local genetic risks that may specifically be identified in Thai population..
100. Yuma Sakamoto, Takuaki Yamamoto, Nobuhiko Sugano, Daisuke Takahashi, Toshiyuki Watanabe, Takashi Atsumi, Junichi Nakamura, Yukiharu Hasegawa, Koichi Akashi, Ichiei Narita, Takeshi Miyamoto, Tsutomu Takeuchi, Katsunori Ikari, Koichi Amano, Atsuhiro Fujie, Toshikazu Kubo, Yoshifumi Tada, Ayumi Kaneuji, Hiroaki Nakamura, Tomoya Miyamura, Tamon Kabata, Ken Yamaji, Takahiro Okawa, Akihiro Sudo, Kenji Ohzono, Yoshiya Tanaka, Yuji Yasunaga, Shuichi Matsuda, Yuuki Imai, Yasuharu Nakashima, Goro Motomura, Satoshi Ikemura, Ryosuke Yamaguchi, Kazuyuki Karasuyama, Kazuhiko Sonoda, Takashi Nishii, Takashi Sakai, Masaki Takao, Tohru Irie, Tsuyoshi Asano, Norimasa Iwasaki, Tatsuya Atsumi, Satoshi Tamaoki, Ryosuke Nakanishi, Satoe Tanabe, Shunji Kishida, Shigeo Hagiwara, Taisuke Seki, Hiroshi Tsukamoto, Hiroaki Niiro, Yojiro Arinobu, Mitsuteru Akahoshi, Hiroshi Mitoma, Masahiro Ayano, Takeshi Kuroda, Yoshiaki Toyama, Atsushi Funayama, Hironari Hanaoka, Kunihiro Yamaoka, Yasushi Kawaguchi, Hisashi Yamanaka, Tetsuji Hosozawa, Shigeki Momohara, Kentaro Chino, Mikihiro Fujioka, Keichiro Ueshima, Masashi Ishida, Masazumi Saito, Shigeki Hayashi, Akira Ikegami, Toru Ichiseki, Shigekazu Mizokawa, Yoichi Ohta, Yoshitomo Kajino, Fumio Sekiya, Fujio Higuchi, Masahiro Hasegawa, Noriki Miyamoto, Shinichi Miyazaki, Toshio Yamaguchi, Wataru Ando, Kazuyoshi Saito, Kazuhisa Nakano, Yutaka Kuroda, Takuma Yamasaki, Masato Akiyama, Michiaki Kubo, Yoichiro Kamatani, Yukihide Iwamoto, Shiro Ikegawa, Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head, Scientific reports, 10.1038/s41598-017-14778-y, 7, 1, 2017.12, Idiopathic osteonecrosis of the femoral head (IONFH) is an ischemic disorder that causes bone necrosis of the femoral head, resulting in hip joint dysfunction. IONFH is a polygenic disease and steroid and alcohol have already known to increase its risk; however, the mechanism of IONFH remains to be elucidated. We performed a genome-wide association study using ~60,000 subjects and found two novel loci on chromosome 20q12 and 12q24. Big data analyses identified LINC01370 as a candidate susceptibility gene in the 20q12 locus. Stratified analysis by IONFH risk factors suggested that the 12q24 locus was associated with IONFH through drinking capacity. Our findings would shed new light on pathophysiology of IONFH..
101. Saori Sakaue, Jun Hirata, Yuichi Maeda, Eiryo Kawakami, Takuro Nii, Toshihiro Kishikawa, Kazuyoshi Ishigaki, Chikashi Terao, Ken Suzuki, Masato Akiyama, Naomasa Suita, Tatsuo Masuda, Kotaro Ogawa, Kenichi Yamamoto, Yukihiko Saeki, Masato Matsushita, Maiko Yoshimura, Hidetoshi Matsuoka, Katsunori Ikari, Atsuo Taniguchi, Hisashi Yamanaka, Hideya Kawaji, Timo Lassmann, Masayoshi Itoh, Hiroyuki Yoshitomi, Hiromu Ito, Koichiro Ohmura, Alistair R.R. Forrest, Yoshihide Hayashizaki, Piero Carninci, Atsushi Kumanogoh, Yoichiro Kamatani, Michiel de Hoon, Kazuhiko Yamamoto, Yukinori Okada, Integration of genetics and miRNA–target gene network identified disease biology implicated in tissue specificity, Nucleic acids research, 10.1093/nar/gky1066, 46, 22, 11898-11909, 2018.01, MicroRNAs (miRNAs) modulate the post-transcriptional regulation of target genes and are related to biology of complex human traits, but genetic landscape of miRNAs remains largely unknown. Given the strikingly tissue-specific miRNA expression profiles, we here expand a previous method to quantitatively evaluate enrichment of genome-wide association study (GWAS) signals on miRNA–target gene networks (MIGWAS) to further estimate tissue-specific enrichment. Our approach integrates tissue-specific expression profiles of miRNAs (∼1800 miRNAs in 179 cells) with GWAS to test whether polygenic signals enrich in miRNA–target gene networks and whether they fall within specific tissues. We applied MIGWAS to 49 GWASs (n Total = 3 520 246), and successfully identified biologically relevant tissues. Further, MIGWAS could point miRNAs as candidate biomarkers of the trait. As an illustrative example, we performed differentially expressed miRNA analysis between rheumatoid arthritis (RA) patients and healthy controls (n = 63). We identified novel biomarker miRNAs (e.g. hsa-miR-762) by integrating differentially expressed miRNAs with MIGWAS results for RA, as well as novel associated loci with significant genetic risk (rs56656810 at MIR762 at 16q11; n = 91 482, P = 3.6 × 10 −8 ). Our result highlighted that miRNA–target gene network contributes to human disease genetics in a cell type-specific manner, which could yield an efficient screening of miRNAs as promising biomarkers..
102. Yoshito Koyanagi, Yusuke Murakami, Jun Funatsu, Masato Akiyama, Shunji Nakatake, Kohta Fujiwara, Takashi Tachibana, Shintaro Nakao, Toshio Hisatomi, Shigeo Yoshida, Tatsuro Ishibashi, Koh Hei Sonoda, Yasuhiro Ikeda, Optical coherence tomography angiography of the macular microvasculature changes in retinitis pigmentosa, Acta Ophthalmologica, 10.1111/aos.13475, 96, 1, e59-e67, 2018.02, Purpose: To investigate the macular microvasculature changes by optical coherence tomography angiography (OCTA) and analyse the correlation between these changes and central visual function in patients with retinitis pigmentosa (RP). Methods: We measured the area of the foveal avascular zone (FAZ) and the foveal and parafoveal flow density (FFD and PFD, respectively) in the superficial (S) and deep (D) retinal plexus by OCTA (AngioVue) and compared these values between 73 RP patients and 36 healthy controls. We analysed the relationships between these microvasculature measurements and central visual functions such as visual acuity (VA) and the values of static perimetry tests (Humphrey Field Analyzer, the central 10–2 program) in the RP patients. Results: The FFD-S, PFD-S and PFD-D were significantly decreased in the RP patients compared to the controls (all p < 0.05), whereas there was no significant difference in the FAZ-S, FAZ-D or FFD-D (all p > 0.05). A subgroup analysis showed that the RP patients with VA <20/20 had increased FAZ-S compared to the controls and RP patients with VA ≥20/20 (p = 0.01 and p = 0.007, respectively). Spearman rank testing demonstrated that PFD-S and PFD-D were significantly correlated with all of the central visual parameters (all p < 0.01). The FAZ-S and FFD-S were significantly correlated with VA, and FAZ-D and FFD-D showed no significant correlation. Conclusion: Both the superficial and deep layers of the parafoveal microvasculature are attenuated in RP and correlated with reduced central visual function. The foveal microvasculature, especially in the deep layer, was relatively preserved until mild-to-moderately advanced stages..
103. M. Ikeda, A. Takahashi, Y. Kamatani, Y. Okahisa, H. Kunugi, N. Mori, T. Sasaki, T. Ohmori, Y. Okamoto, H. Kawasaki, S. Shimodera, T. Kato, H. Yoneda, R. Yoshimura, M. Iyo, K. Matsuda, M. Akiyama, K. Ashikawa, K. Kashiwase, K. Tokunaga, K. Kondo, T. Saito, A. Shimasaki, K. Kawase, T. Kitajima, K. Matsuo, M. Itokawa, T. Someya, T. Inada, R. Hashimoto, T. Inoue, K. Akiyama, H. Tanii, H. Arai, S. Kanba, N. Ozaki, I. Kusumi, T. Yoshikawa, M. Kubo, N. Iwata, A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder, Molecular Psychiatry, 10.1038/mp.2016.259, 23, 3, 639-647, 2018.03, Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10 '9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (P best =5.8 × 10 '10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (P best =1.9 × 10 '9), TRANK1 (P best =2.1 × 10 '9) and ODZ4 (P best =3.3 × 10 '9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', P best ∼10 '29, R 2 ∼2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' P best ∼10 '13, R 2 ∼0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates∼0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations..
104. Shiga Y*, Akiyama M*, Nishiguchi KM, Sato K, Shimozawa N, Takahashi A, Momozawa Y, Hirata M, Matsuda K, Yamaji T, Iwasaki M, Tsugane S, Oze I, Mikami H, Naito M, Wakai K, Yoshikawa M, Miyake M, Yamashiro K, Japan Glaucoma Society Omics Group: Kashiwagi K, Iwata T, Mabuchi F, Takamoto M, Ozaki M, Kawase K, Aihara M, Araie M, Yamamoto T, Kiuchi Y, Nakamura M, Ikeda Y, Sonoda KH, Ishibashi T, Nitta K, Iwase A, Shirato S, Oka Y, Satoh M, Sasaki M, Fuse N, Suzuki Y, Cheng CY, Khor CC, Baskaran M, Perera S, Aung T, Vithana EN, Cooke Bailey JN, Kang JH, Pasquale LR, Haines JL, NEIGHBORHOOD consortium, Wiggs JL, Burdon KP, Gharahkhani P, Hewitt AW, Mackey DA, MacGregor S, Craig JE, Allingham RR, Hauser M, Ashaye A, Budenz DL, Akafo S, Williams SE, Kamatani Y, Nakazawa T, Kubo M., Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma, Human Molecular Genetics, 10.1093/hmg/ddy053, 27, 8, 1486-1496, 2018.04.
105. Asahi Hishida, Masahiro Nakatochi, Masato Akiyama, Yoichiro Kamatani, Takeshi Nishiyama, Hidemi Ito, Isao Oze, Yuichiro Nishida, Megumi Hara, Naoyuki Takashima, Tanvir Chowdhury Turin, Miki Watanabe, Sadao Suzuki, Rie Ibusuki, Ippei Shimoshikiryo, Yohko Nakamura, Haruo Mikami, Hiroaki Ikezaki, Norihiro Furusyo, Kiyonori Kuriki, Kaori Endoh, Teruhide Koyama, Daisuke Matsui, Hirokazu Uemura, Kokichi Arisawa, Tae Sasakabe, Rieko Okada, Sayo Kawai, Mariko Naito, Yukihide Momozawa, Michiaki Kubo, Kenji Wakai, Genome-Wide Association Study of Renal Function Traits
Results from the Japan Multi-Institutional Collaborative Cohort Study, American Journal of Nephrology, 10.1159/000488946, 47, 5, 304-316, 2018.06, Background: Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide. Methods: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects. Results: In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of -activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10-6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10-8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations. Conclusion: Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations..
106. Masato Akiyama, Atsushi Takahashi, Yukihide Momozawa, Satoshi Arakawa, Fuyuki Miya, Tatsuhiko Tsunoda, Kyota Ashikawa, Yuji Oshima, Miho Yasuda, Shigeo Yoshida, Hiroshi Enaida, Xue Tan, Yasuo Yanagi, Tsutomu Yasukawa, Yuichiro Ogura, Yoshimi Nagai, Kanji Takahashi, Kimihiko Fujisawa, Maiko Inoue, Akira Arakawa, Koji Tanaka, Mitsuko Yuzawa, Kazuaki Kadonosono, Koh Hei Sonoda, Tatsuro Ishibashi, Michiaki Kubo, Genome-wide association study suggests four variants influencing outcomes with ranibizumab therapy in exudative age-related macular degeneration, Journal of Human Genetics, 10.1038/s10038-018-0493-0, 63, 10, 1083-1091, 2018.10, To identify factors associated with ranibizumab responses in patients with exudative age-related macular degeneration (AMD), we performed a genome-wide association study (GWAS) and a replication study using a total of 919 exudative AMD patients treated with intravitreal ranibizumab in a Japanese population. In the combined analysis of GWAS and the replication study, no loci reached genome-wide significant level; however, we found four variants showed suggestive level of associations with visual loss at month three (rs17822656, rs76150532, rs17296444, and rs75165563: Pcombined < 1.0 × 10−5). Of the candidate genes within these loci, three were relevant to VEGF-related pathway (KCNMA1, SOCS2, and OTX2). The proportions of patients who worsened visual acuity were 13.7%, 38.8%, 58.0%, and 80.0% in patients with 0, 1, 2, and 3 or more identified risk variants, respectively. Changes in visual acuity decreased linearly as the number of risk variants increased (P = 1.67 × 10–12). The area under the curve using age, baseline visual acuity, and history of previous treatment was 0.607, and improved significantly to 0.713 in combination with identified variants (P < 0.0001). Although further study is needed to confirm their associations, our results offer candidate variants influencing response to ranibizumab therapy..
107. Han B*, Akiyama M*, Kim KK, Oh H, Choi H, Lee CH, Jung S, Lee HS, Kim EE, Cook S, Haritunians T, Yamazaki K, Park SH, Ye BD, McGovern DPB, Esaki M, Kawaguchi T, Khor SS, Taylor KD, Rotter JI, Suzuki Y, Matsui T, Motoya S, Bang SY, Kim TH, Momozawa Y, Kamatani Y, Tokunaga K, Kubo M, Okada Y, Yang SK, Song K., Amino acid position 37 of HLA-DR beta 1 affects susceptibility to Crohn's disease in Asians, Human Molecular Genetics, 10.1093/hmg/ddy285, 27, 22, 3901-3910, 2018.11.
108. Yukinori Okada, Yukihide Momozawa, Saori Sakaue, Masahiro Kanai, Kazuyoshi Ishigaki, Masato Akiyama, Toshihiro Kishikawa, Yasumichi Arai, Takashi Sasaki, Kenjiro Kosaki, Makoto Suematsu, Koichi Matsuda, Kazuhiko Yamamoto, Michiaki Kubo, Nobuyoshi Hirose, Yoichiro Kamatani, Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese, Nature communications, 10.1038/s41467-018-03274-0, 9, 1, 2018.12, Understanding natural selection is crucial to unveiling evolution of modern humans. Here, we report natural selection signatures in the Japanese population using 2234 high-depth whole-genome sequence (WGS) data (25.9×). Using rare singletons, we identify signals of very recent selection for the past 2000-3000 years in multiple loci (ADH cluster, MHC region, BRAP-ALDH2, SERHL2). In large-scale genome-wide association study (GWAS) dataset (n = 171,176), variants with selection signatures show enrichment in heterogeneity of derived allele frequency spectra among the geographic regions of Japan, highlighted by two major regional clusters (Hondo and Ryukyu). While the selection signatures do not show enrichment in archaic hominin-derived genome sequences, they overlap with the SNPs associated with the modern human traits. The strongest overlaps are observed for the alcohol or nutrition metabolism-related traits. Our study illustrates the value of high-depth WGS to understand evolution and their relationship with disease risk..
109. Alexander Teumer, Layal Chaker, Stefan Groeneweg, Yong Li, Celia Di Munno, Caterina Barbieri, Ulla T. Schultheiss, Michela Traglia, Tarunveer S. Ahluwalia, Masato Akiyama, Emil Vincent R. Appel, Dan E. Arking, Alice Arnold, Arne Astrup, Marian Beekman, John P. Beilby, Sofie Bekaert, Eric Boerwinkle, Suzanne J. Brown, Marc De Buyzere, Purdey J. Campbell, Graziano Ceresini, Charlotte Cerqueira, Francesco Cucca, Ian J. Deary, Joris Deelen, Kai Uwe Eckardt, Arif B. Ekici, Johan G. Eriksson, Luigi Ferrrucci, Tom Fiers, Edoardo Fiorillo, Ian Ford, Caroline S. Fox, Christian Fuchsberger, Tessel E. Galesloot, Christian Gieger, Martin Gögele, Alessandro De Grandi, Niels Grarup, Karin Halina Greiser, Kadri Haljas, Torben Hansen, Sarah E. Harris, Diana van Heemst, Martin den Heijer, Andrew A. Hicks, Wouter den Hollander, Georg Homuth, Jennie Hui, Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation, Nature communications, 10.1038/s41467-018-06356-1, 9, 1, 2018.12, Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets..
110. Jun Funatsu, Yusuke Murakami, Shunji Nakatake, Masato Akiyama, Kohta Fujiwara, Shotaro Shimokawa, Takashi Tachibana, Toshio Hisatomi, Yoshito Koyanagi, Yukihide Momozawa, Koh Hei Sonoda, Yasuhiro Ikeda, Direct comparison of retinal structure and function in retinitis pigmentosa by co-registering microperimetry and optical coherence tomography, PloS one, 10.1371/journal.pone.0226097, 14, 12, 2019.01, Purpose To evaluate the retinal structure-function relationships in the macula of retinitis pigmentosa (RP) patients by comparing microperimetry-3 (MP-3) images with co-registered optical coherence tomography (OCT) images. Methods Thirty patients with typical RP were recruited from our hospital. The maculae of patients were examined with MP-3 and OCT. The retinal sensitivity was measured by MP-3 at 40 testing points arranged concentrically in a 16∘ diameter of the central retina, and we divided the 40 points into four zones according to degree from the fovea (2∘, 4∘, 6∘, and 8∘). We analyzed the correlation coefficients between the retinal sensitivity and the total retinal thickness (TRT), the length from the inner limiting membrane to the retinal pigment epithelium (RPE), and between the retinal sensitivity and the outer retinal thickness (ORT), the length from the outer plexiform layer to the RPE at each stimulus point. Results TRT showed moderate correlations with the retinal sensitivity at 2∘ (median ρ = 0.59 interquartile range (IQR) [0.38–0.72]), 4∘ (ρ = 0.59 [0.55–0.68]) and 6∘ (ρ = 0.60 [0.54–0.63]), and TRT was weakly-to-moderately related to the retinal sensitivity at 8∘ (ρ = 0.27 [0.19–0.48]). ORT exhibited strong correlations at 2∘ (ρ = 0.72 [0.60–0.81]), 4∘ (ρ = 0.71 [0.75–0.67]) and 6∘ (ρ = 0.70 [0.54–0.74]), and a weak-to-moderate correlations at 8∘ (ρ = 0.34 [0.29–0.53]). ORT was more strongly correlated with the retinal sensitivity compared to TRT (p = 0.018). Conclusion ORT, rather than TRT, within 6∘ eccentricity was strongly correlated with the retinal sensitivity, suggesting that measuring ORT in those areas will help evaluate the macular status and progression in RP..
111. Masataka Ishizu, Yusuke Murakami, Kohta Fujiwara, Jun Funatsu, Shotaro Shimokawa, Shunji Nakatake, Takashi Tachibana, Toshio Hisatomi, Yoshito Koyanagi, Masato Akiyama, Yukihide Momozawa, Tatsuro Ishibashi, Koh Hei Sonoda, Yasuhiro Ikeda, Relationships between serum antioxidant and oxidant statuses and visual function in retinitis pigmentosa, Investigative Ophthalmology and Visual Science, 10.1167/iovs.19-26927, 60, 13, 4462-4468, 2019.01, PURPOSE. To investigate the serum changes of antioxidant/oxidant markers and the relationship between these factors and visual function in patients with retinitis pigmentosa (RP). METHODS. Fifty-two RP patients <40 years old and 25 controls were included. Serum samples were analyzed for superoxide dismutase 3 (SOD3) activity, glutathione peroxidase (GPx), potential antioxidant (PAO), and hexanoyl-lysine (HEL). The relationships between these markers and visual parameters, including best-corrected visual acuity (BCVA), mean deviation (MD), and average retinal sensitivity of 4 or 12 central points on static perimetry tests (Humphrey Field Analyzer, the central 10–2 program) were examined in the RP patients. RESULTS. Although there was no significant difference in the serum SOD3 activity between RP patients and controls, serum SOD3 activity in the severe degeneration group with macular involvement (16.3 6 11.3 U/mL) was significantly lower compared with those in the mild degeneration group (those with midperipheral scotomas; 28.5 6 16.6 U/mL, P ¼ 0.0459). SOD3 was significantly related to visual acuity (r ¼ -0.3701, P ¼ 0.0069) and the average retinal sensitivity of four central points (r ¼ 0.3463, P ¼ 0.0137) in RP patients. The linear trends of these two parameters across SOD3 levels were also significant (P ¼ 0.0264 and 0.0172, respectively). There was no consistent correlation between other serum antioxidant/ oxidant markers and visual parameters. CONCLUSIONS. Lower serum SOD3 activity was associated with the severe retinal degeneration in RP patients. Our results suggest that serum SOD3 activity may be related to disease severity in RP..
112. Jun Hirata, Kazuyoshi Hosomichi, Saori Sakaue, Masahiro Kanai, Hirofumi Nakaoka, Kazuyoshi Ishigaki, Ken Suzuki, Masato Akiyama, Toshihiro Kishikawa, Kotaro Ogawa, Tatsuo Masuda, Kenichi Yamamoto, Makoto Hirata, Koichi Matsuda, Yukihide Momozawa, Ituro Inoue, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Genetic and phenotypic landscape of the major histocompatibilty complex region in the Japanese population, Nature genetics, 10.1038/s41588-018-0336-0, 51, 3, 470-480, 2019.03, To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data (n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals. A phenome-wide association study assessing 106 clinical phenotypes identified abundant, significant genotype–phenotype associations across 52 phenotypes. Fine-mapping highlighted multiple association patterns conferring independent risks from classical HLA genes. Region-wide heritability estimates and genetic-correlation network analysis elucidated the polygenic architecture shared across the phenotypes..
113. Matthias Wuttke, Yong Li, Man Li, Karsten B. Sieber, Mary F. Feitosa, Mathias Gorski, Adrienne Tin, Lihua Wang, Audrey Y. Chu, Anselm Hoppmann, Holger Kirsten, Ayush Giri, Jin Fang Chai, Gardar Sveinbjornsson, Bamidele O. Tayo, Teresa Nutile, Christian Fuchsberger, Jonathan Marten, Massimiliano Cocca, Sahar Ghasemi, Yizhe Xu, Katrin Horn, Damia Noce, Peter J. van der Most, Sanaz Sedaghat, Zhi Yu, Masato Akiyama, Saima Afaq, Tarunveer S. Ahluwalia, Peter Almgren, Najaf Amin, Ärnlöv Johan, Stephan J.L. Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L. Biggs, Ginevra Biino, Michael Boehnke, Eric Boerwinkle, Mathilde Boissel, Erwin P. Bottinger, Thibaud S. Boutin, Hermann Brenner, Marco Brumat, Ralph Burkhardt, Adam S. Butterworth, Eric Campana, Archie Campbell, Harry Campbell, A catalog of genetic loci associated with kidney function from analyses of a million individuals, Nature genetics, 10.1038/s41588-019-0407-x, 51, 6, 957-972, 2019.06, Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research..
114. Jun Inaishi, Yoichiro Hirakawa, Momoko Horikoshi, Masato Akiyama, Mayu Higashioka, Masahito Yoshinari, Jun Hata, Naoko Mukai, Yoichiro Kamatani, Yukihide Momozawa, Michiaki Kubo, Toshiharu Ninomiya, Association between Genetic Risk and Development of Type 2 Diabetes in a General Japanese Population
The Hisayama Study, Journal of Clinical Endocrinology and Metabolism, 10.1210/jc.2018-01782, 104, 8, 3213-3222, 2019.06, Context Although recent genetic studies have identified many susceptibility loci associated with type 2 diabetes (T2D), the usefulness of such loci for precision medicine remains uncertain. Objective This study investigated the impact of genetic risk score (GRS) on the development of T2D in a general Japanese population. Participants The current study consists of 1465 subjects aged 40 to 79 years without diabetes who underwent a health examination in 2002. Design The GRS was generated using the literature-based effect size for T2D of 84 susceptibility loci for the Japanese population, and the risk estimates of GRS on the incidence of T2D were computed by using a Cox proportional hazard model in a 10-year follow-up study. The influence of GRS on the predictive ability was estimated with Harrell C statistics, integrated discrimination improvement (IDI), and continuous net reclassification improvement (cNRI). Results During the 10-year follow-up, 199 subjects experienced T2D. The risk of developing T2D increased significantly with elevating quintiles of GRS (multivariable-adjusted hazard ratio for the fifth vs first quintile, 2.85; 95% CI, 1.83 to 4.44). When incorporating GRS into the multivariable model comprising environmental risk factors, the Harrell C statistics (95% CI) increased from 0.681 (0.645 to 0.717) to 0.707 (0.672 to 0.742) and the predictive ability of T2D was significantly improved (IDI, 0.0376; 95% CI, 0.0284 to 0.0494; cNRI, 0.3565; 95% CI, 0.1278 to 0.5829). GRS was also associated with the risk of T2D independently of environmental risk factors. Conclusions These findings suggest the usefulness of GRS for identifying a high-risk population together with environmental risk factors in the Japanese population..
115. Shunji Nakatake, Yusuke Murakami, Jun Funatsu, Yoshito Koyanagi, Masato Akiyama, Yukihide Momozawa, Tatsuro Ishibashi, Koh Hei Sonoda, Yasuhiro Ikeda, Early detection of cone photoreceptor cell loss in retinitis pigmentosa using adaptive optics scanning laser ophthalmoscopy, Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 10.1007/s00417-019-04307-0, 257, 6, 1169-1181, 2019.06, PURPOSE: The purpose of the study was to investigate the characteristics of the parafoveal cone density changes in patients with retinitis pigmentosa (RP) using adaptive optics scanning laser ophthalmoscopy (AO-SLO). METHODS: A total of 14 eyes of RP patients and 10 eyes of control subjects were examined. High-resolution images of cone photoreceptor cells were obtained with a Canon AO-SLO system in the four retinal regions of the superior, inferior, temporal, and nasal areas located 1.0 mm from the central fovea. The relationships of cone density with optical coherence tomography (OCT) findings and the visual sensitivity of the static perimetry tests were analyzed in RP patients. RESULTS: The averaged cone densities in RP patients were decreased at 1.0 mm eccentricity from the fovea (11,899 cells/mm2) compared with those in control subjects (16,647 cells/mm2; P < 0.01). The cone density was substantially decreased even in RP patients with an intact interdigitation zone at the examined area (12,865 cells/mm2; P < 0.01 vs. controls) and preserved visual sensitivity with > 35 dB (13,019 cells/mm2; P < 0.001 vs. controls). CONCLUSIONS: In RP, cone photoreceptor cell loss occurred in the parafoveal region with a preserved EZ/IZ or visual sensitivity. AO-SLO may be a useful modality to detect early changes of cone photoreceptor cells in RP patients..
116. Tao Huang, Tiange Wang, Yan Zheng, Christina Ellervik, Xiang Li, Meng Gao, Zhe Fang, Jin Fang Chai, Tarun Veer S. Ahluwalia, Yujie Wang, Trudy Voortman, Raymond Noordam, Alexis Frazier-Wood, Markus Scholz, Emily Sonestedt, Masato Akiyama, Rajkumar Dorajoo, Ang Zhou, Tuomas O. Kilpeläinen, Marcus E. Kleber, Sarah R. Crozier, Keith M. Godfrey, Rozenn Lemaitre, Janine F. Felix, Yuan Shi, Preeti Gupta, Chiea Chuen Khor, Terho Lehtimäki, Carol A. Wang, Carla M.T. Tiesler, Elisabeth Thiering, Marie Standl, Peter Rzehak, Eirini Marouli, Meian He, Cécile Lecoeur, Dolores Corella, Chao Qiang Lai, Luis A. Moreno, Niina Pitkänen, Colin A. Boreham, Tao Zhang, Seang Mei Saw, Paul M. Ridker, Mariaelisa Graff, Frank J.A. van Rooij, Andre G. Uitterlinden, Albert Hofman, Diana van Heemst, Frits R. Rosendaal, Association of Birth Weight With Type 2 Diabetes and Glycemic Traits
A Mendelian Randomization Study, JAMA network open, 10.1001/jamanetworkopen.2019.10915, 2, 9, e1910915, 2019.09, Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures: Type 2 diabetes and glycemic traits. Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (β = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms..
117. Yoshito Koyanagi, Masato Akiyama, Koji M. Nishiguchi, Yukihide Momozawa, Yoichiro Kamatani, Sadaaki Takata, Chihiro Inai, Yusuke Iwasaki, Mikako Kumano, Yusuke Murakami, Kazuko Omodaka, Toshiaki Abe, Shiori Komori, Dan Gao, Toshiaki Hirakata, Kentaro Kurata, Katsuhiro Hosono, Shinji Ueno, Yoshihiro Hotta, Akira Murakami, Hiroko Terasaki, Yuko Wada, Toru Nakazawa, Tatsuro Ishibashi, Yasuhiro Ikeda, Michiaki Kubo, Koh Hei Sonoda, Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients, Journal of medical genetics, 10.1136/jmedgenet-2018-105691, 56, 10, 662-670, 2019.10, Background The genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population. Methods A total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases. Results We successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935∗)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658∗) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases. Conclusions East Asian-specific variants in causative genes were the major causes of RP in the Japanese population..
118. Tin A, Marten J, Halperin Kuhns VL, Wuttke M, Kirsten H, Sieber KB, Qiu C, Gorski M, Yu Z, Giri A, Svrinbjornsson G, Li M, Chu AY, Hoppmann A, O'Connor LJ, Prins B, Nutile T, Noce D, Akiyama M, Cocca M, Ghasemi S, van der Most PJ, Horn K, Xu Y, Fuchsberger C, Sedaghat S, Afaq S, Amin N, Ärnlöv J, Bakker SJL, Bansal N, Baptista D, Bergmann S, Biggs ML, Biino G, Boerwinkle E, Bottinger EP, Boutin TS, Brumat M, Burkhardt R, Campana E, Campbell A, Campbell H, Carroll RJ, Catamo E, Chambers JC, Ciullo M, Concas MP, Coresh J, Corre T, Cusi D, Felicita SC, de Borst MH, De Grandi A, de Mutsert R, de Vries APJ, Delgado G, Demirkan A, Devuyst O, Dittrich K, Eckardt KU, Ehret G, Endlich K, Evans MK, Gansevoort RT, Gasparini P, Giedraitis V, Gieger C, Girotto G, Gögele M, Gordon SD, Gudbjartsson DF, Gudnason V; German Chronic Kidney Disease Study, Haller T, Hamet P, Harris TB, Hayward C, Hicks AA, Hofer E, Holm H, Huang W, Hutri-Kähönen N, Hwang SJ, Ikram MA, Lewis RM, Ingelsson E, Jakobsdottir J, Jonsdottir I, Jonsson H, Joshi PK, Josyula NS, Jung B, Kähönen M, Kamatani Y, Kanai M, Kerr SM, Kiess W, Kleber ME, Koenig W, Kooner JS, Körner A, Kovacs P, Krämer BK, Kronenberg F, Kubo M, Kühnel B, La Bianca M, Lange LA, Lehne B, Lehtimäki T; Lifelines Cohort Study, Liu J, Loeffler M, Loos RJF, Lyytikäinen LP, Magi R, Mahajan A, Martin NG, März W, Mascalzoni D, Matsuda K, Meisinger C, Meitinger T, Metspalu A, Milaneschi Y; V. A. Million Veteran Program, O'Donnell CJ, Wilson OD, Gaziano JM, Mishra PP, Mohlke KL, Mononen N, Montgomery GW, Mook-Kanamori DO, Müller-Nurasyid M, Nadkarni GN, Nalls MA, Nauck M, Nikus K, Ning B, Nolte IM, Noordam R, O'Connell JR, Olafsson I, Padmanabhan S, Penninx BWJH, Perls T, Peters A, Pirastu M, Pirastu N, Pistis G, Polasek O, Ponte B, Porteous DJ, Poulain T, Preuss MH, Rabelink TJ, Raffield LM, Raitakari OT, Rettig R, Rheinberger M, Rice KM, Rizzi F, Robino A, Rudan I, Krajcoviechova A, Cifkova R, Rueedi R, Ruggiero D, Ryan KA, Saba Y, Salvi E, Schmidt H, Schmidt R, Shaffer CM, Smith AV, Smith BH, Spracklen CN, Strauch K, Stumvoll M, Sulem P, Tajuddin SM, Teren A, Thiery J, Thio CHL, Thorsteinsdottir U, Toniolo D, Tönjes A, Tremblay J, Uitterlinden AG, Vaccargiu S, van der Harst P, van Duijn CM, Verweij N, Völker U, Vollenweider P, Waeber G, Waldenberger M, Whitfield JB, Wild SH, Wilson JF, Yang Q, Zhang W, Zonderman AB, Bochud M, Wilson JG, Pendergrass SA, Ho K, Parsa A, Pramstaller PP, Psaty BM, Böger CA, Snieder H, Butterworth AS, Okada Y, Edwards TL, Stefansson K, Susztak K, Scholz M, Heid IM, Hung AM, Teumer A, Pattaro C, Woodward OM, Vitart V, Köttgen A., Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels, Nature genetics, 10.1038/s41588-019-0504-x, 51, 10, 1459-1474, 2019.10, Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits..
119. Ikuo Otsuka, Masato Akiyama, Osamu Shirakawa, Satoshi Okazaki, Yukihide Momozawa, Yoichiro Kamatani, Takeshi Izumi, Shusuke Numata, Motonori Takahashi, Shuken Boku, Ichiro Sora, Ken Yamamoto, Yasuhiro Ueno, Tatsushi Toda, Michiaki Kubo, Akitoyo Hishimoto, Genome-wide association studies identify polygenic effects for completed suicide in the Japanese population, Neuropsychopharmacology, 10.1038/s41386-019-0506-5, 44, 12, 2119-2124, 2019.11, Suicide is a significant public health problem worldwide, and several Asian countries including Japan have relatively high suicide rates on a world scale. Twin, family, and adoption studies have suggested high heritability for suicide, but genetics lags behind due to difficulty in obtaining samples from individuals who died by suicide, especially in non-European populations. In this study, we carried out genome-wide association studies combining two independent datasets totaling 746 suicides and 14,049 non-suicide controls in the Japanese population. Although we identified no genome-wide significant single-nucleotide polymorphisms (SNPs), we demonstrated significant SNP-based heritability (35–48%; P < 0.001) for completed suicide by genomic restricted maximum-likelihood analysis and a shared genetic risk between two datasets (Pbest = 2.7 × 10−13) by polygenic risk score analysis. This study is the first genome-wide association study for suicidal behavior in an East Asian population, and our results provided the evidence of polygenic architecture underlying completed suicide..
120. Koji M. Nishiguchi, Yasuhiro Ikeda, Kosuke Fujita, Hiroshi Kunikata, Makoto Akiho, Kazuki Hashimoto, Katsuhiro Hosono, Kentaro Kurata, Yoshito Koyanagi, Masato Akiyama, Takefumi Suzuki, Ryo Kawasaki, Yuko Wada, Yoshihiro Hotta, Koh Hei Sonoda, Akira Murakami, Mitsuru Nakazawa, Toru Nakazawa, Toshiaki Abe, Phenotypic Features of Oguchi Disease and Retinitis Pigmentosa in Patients with S-Antigen Mutations
A Long-Term Follow-up Study, Ophthalmology, 10.1016/j.ophtha.2019.05.027, 126, 11, 1557-1566, 2019.11, Purpose: To present phenotypic features of 22 patients with S-antigen (SAG) mutations. Design: Retrospective cohort study. Participants: Twenty-one Japanese patients from 16 families with a homozygous c.924delA mutation and 1 patient with a homozygous c.636delT mutation in the SAG gene. Methods: Clinical records on symptoms; best-corrected visual acuity; and Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), OCT, and electroretinography results were reviewed. Main Outcome Measures: Best-corrected visual acuity, Goldmann perimetry results, imaging findings, and electroretinography results. Results: Ten patients had Oguchi disease and 12 had retinitis pigmentosa (RP) with mean follow-up periods of 13.8 and 10.2 years, respectively. Retinitis pigmentosa patients were older (mean age, 56.0 years) than those with Oguchi disease (mean age, 22.1 years; P < 0.001) at the initial visit. Night blindness noted in childhood was the most common initial symptom for both Oguchi disease (80.0%) and RP (91.7%) patients. Best-corrected visual acuity in the logarithm of the minimum angle of resolution (logMAR) was well preserved in Oguchi disease patients (mean, 0.02 logMAR in both eyes) but reduced in most RP patients (mean, 1.32 logMAR [right eye] and 1.35 logMAR [left eye]). Similarly, the visual field in the retinal area was preserved in Oguchi disease patients (mean, 677 mm2 right eye and 667 mm2 left eye) and reduced in RP patients (mean, 369 mm2 right eye and 294 mm2 left eye). Fundus images revealed a characteristic golden sheen with no retinal degeneration in Oguchi disease patients, excluding 2 with macular degeneration detected by FAF, OCT, or both and 1 with mild retinal degeneration confirmed by OCT and fluorescein angiography. Pigmentary retinal degeneration most evident posteriorly was observed in RP patients, accompanied by a characteristic golden sheen in 12 of 14 patients undergoing ultra-widefield fundus imaging. OCT showed disrupted macular structure, and FAF revealed variable hypofluorescence. Electroretinography identified absent rod responses in both diseases, along with relative preservation of cone responses in Oguchi disease patients. Three patients showed progressive loss of the golden sheen based on fundus images, including 1 who demonstrated RP 26 years after the initial diagnosis of Oguchi disease. Conclusions: Retinitis pigmentosa with SAG mutations often shows a characteristic golden sheen surrounding posterior pigmentary retinal degeneration. Oguchi disease can show progressive degeneration in adulthood, rarely resulting in RP..
121. Konstantinos Nikopoulos, Katarina Cisarova, Mathieu Quinodoz, Hanna Koskiniemi-Kuendig, Noriko Miyake, Pietro Farinelli, Atta Ur Rehman, Muhammad Imran Khan, Andrea Prunotto, Masato Akiyama, Yoichiro Kamatani, Chikashi Terao, Fuyuki Miya, Yasuhiro Ikeda, Shinji Ueno, Nobuo Fuse, Akira Murakami, Yuko Wada, Hiroko Terasaki, Koh Hei Sonoda, Tatsuro Ishibashi, Michiaki Kubo, Frans P.M. Cremers, Zoltán Kutalik, Naomichi Matsumoto, Koji M. Nishiguchi, Toru Nakazawa, Carlo Rivolta, A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy, Nature communications, 10.1038/s41467-019-10746-4, 10, 1, 2019.12, Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10−5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance..
122. David W. Clark, Yukinori Okada, Kristjan H.S. Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L.K. Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M. Bartz, Clemens Baumbach, Ginevra Biino, Matthew J. Bixley, Marco Brumat, Jin Fang Chai, Tanguy Corre, Diana L. Cousminer, Annelot M. Dekker, David A. Eccles, Kristel R. van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D. Gordon, Hugoline G. de Haan, Sarah E. Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E. Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E. Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E. Montasser, Peter J. van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B. Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R. Sapkota, Daniel Shriner, Line Skotte, Melissa C. Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N. Spracklen, Rona J. Strawbridge, Salman M. Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R. Warren, Robyn E. Wootton, Lisa R. Yanek, Jie Yao, Noha A. Yousri, Wei Zhao, Adebowale A. Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L. Albert, Matthew A. Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R. Bentley, Heiner Boeing, Eric Boerwinkle, Judith B. Borja, Gert J. de Borst, Erwin P. Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao Li Chee, Guanjie Chen, Yii Der I. Chen, Zhengming Chen, Yen Feng Chiu, Massimiliano Cocca, Francis S. Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M. van Dam, Anna Damulina, Maryam S. Daneshpour, Felix R. Day, Graciela E. Delgado, Klodian Dhana, Alexander S.F. Doney, Marcus Dörr, Ayo P. Doumatey, Nduna Dzimiri, S. Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F. Felix, Krista Fischer, Barry I. Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O. Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F. Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P. Hagenaars, Christopher A. Haiman, Avner Halevy, Tamara B. Harris, Mehdi Hedayati, David A. van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi Jen Hung, M. Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D. Kerrison, Thorsten Kessler, Kay Tee Khaw, Chiea Chuen Khor, Dominique P.V. de Kleijn, Woon Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K. Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J. Launer, Deborah A. Lawlor, I. Te Lee, Wen Jane Lee, Markus M. Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J. London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W. Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W. Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y. Millwood, Yukihide Momozawa, Amy Moore, Pierre Emmanuel Morange, Hortensia Moreno-Macías, Trevor A. Mori, Alanna C. Morrison, Taulant Muka, Yoshinori Murakami, Alison D. Murray, Renée de Mutsert, Josyf C. Mychaleckyj, Mike A. Nalls, Matthias Nauck, Matt J. Neville, Ilja M. Nolte, Ken K. Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S. Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P. Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C. Rao, Wouter van Rheenen, Stephen S. Rich, Paul M. Ridker, Cornelius A. Rietveld, Antonietta Robino, Frank J.A. van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J. Scott, William R. Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J. Sever, Wayne H.H. Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K. Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H. Smith, Alena Stančáková, Alice Stanton, John M. Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A. Swertz, Adele M. Taylor, Kent D. Taylor, Natalie Terzikhan, Yih Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P. Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H. Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M. Wakil, Melanie Waldenberger, Gurpreet S. Wander, Ya Xing Wang, Nicholas J. Wareham, Sarah Wild, Chittaranjan S. Yajnik, Jian Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W. Asselbergs, Stephan J.L. Bakker, Diane M. Becker, Benjamin Lehne, David A. Bennett, Leonard H. van den Berg, Sonja I. Berndt, Dwaipayan Bharadwaj, Lawrence F. Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P. Bradfield, Jennifer A. Brody, Archie Campbell, Shai Carmi, Mark J. Caulfield, David Cesarini, John C. Chambers, Giriraj Ratan Chandak, Ching Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J. Deary, Rajkumar Dorajoo, Cornelia M. van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G. Eriksson, Evangelos Evangelou, Michele K. Evans, Jessica D. Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F.A. Grant, Lyn R. Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew Kiat Heng, Andrew A. Hicks, Hagit Hochner, Heikki Huikuri, Steven C. Hunt, Vincent W.V. Jaddoe, Philip L. De Jager, Magnus Johannesson, Åsa Johansson, Jost B. Jonas, J. Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L.R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W. van der Laan, Jari Lahti, Matthias Laudes, Rodney A. Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G. Martin, Winfried März, Giuseppe Matullo, Mark I. McCarthy, Sarah E. Medland, Tony R. Merriman, Andres Metspalu, Brian F. Meyer, Karen L. Mohlke, Grant W. Montgomery, Dennis Mook-Kanamori, Patricia B. Munroe, Kari E. North, Dale R. Nyholt, Jeffery R. O’connell, Carole Ober, Albertine J. Oldehinkel, Walter Palmas, Colin Palmer, Gerard G. Pasterkamp, Etienne Patin, Craig E. Pennell, Louis Perusse, Patricia A. Peyser, Mario Pirastu, Tinca J.C. Polderman, David J. Porteous, Danielle Posthuma, Bruce M. Psaty, John D. Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I. Rotter, Igor Rudan, Hester M. Den Ruijter, Dharambir K. Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B. Schulze, Heribert Schunkert, Robert A. Scott, Alan R. Shuldiner, Xueling Sim, Neil Small, Jennifer A. Smith, Nona Sotoodehnia, E. Shyong Tai, Alexander Teumer, Nicholas J. Timpson, Daniela Toniolo, David Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A. Wang, David R. Weir, John B. Whitfield, Cisca Wijmenga, Tien Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S. Zemel, Alan B. Zonderman, Markus Perola, Patrik K.E. Magnusson, André G. Uitterlinden, Jaspal S. Kooner, Daniel I. Chasman, Ruth J.F. Loos, Nora Franceschini, Lude Franke, Chris S. Haley, Caroline Hayward, Robin G. Walters, John R.B. Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K. Joshi, Michiaki Kubo, James F. Wilson, Associations of autozygosity with a broad range of human phenotypes, Nature communications, 10.1038/s41467-019-12283-6, 10, 1, 2019.12, In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding..
123. Chikashi Terao, Yukihide Momozawa, Kazuyoshi Ishigaki, Eiryo Kawakami, Masato Akiyama, Po Ru Loh, Giulio Genovese, Hiroki Sugishita, Tazro Ohta, Makoto Hirata, John R.B. Perry, Koichi Matsuda, Yoshinori Murakami, Michiaki Kubo, Yoichiro Kamatani, GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation, Nature communications, 10.1038/s41467-019-12705-5, 10, 1, 2019.12, Mosaic loss of chromosome Y (mLOY) is frequently observed in the leukocytes of ageing men. However, the genetic architecture and biological mechanisms underlying mLOY are not fully understood. In a cohort of 95,380 Japanese men, we identify 50 independent genetic markers in 46 loci associated with mLOY at a genome-wide significant level, 35 of which are unreported. Lead markers overlap enhancer marks in hematopoietic stem cells (HSCs, P ≤ 1.0 × 10−6). mLOY genome-wide association study signals exhibit polygenic architecture and demonstrate strong heritability enrichment in regions surrounding genes specifically expressed in multipotent progenitor (MPP) cells and HSCs (P ≤ 3.5 × 10−6). ChIP-seq data demonstrate that binding sites of FLI1, a fate-determining factor promoting HSC differentiation into platelets rather than red blood cells (RBCs), show a strong heritability enrichment (P = 1.5 × 10−6). Consistent with these findings, platelet and RBC counts are positively and negatively associated with mLOY, respectively. Collectively, our observations improve our understanding of the mechanisms underlying mLOY..
124. Masahiro Nakatochi, Masahiro Kanai, Akiyoshi Nakayama, Asahi Hishida, Yusuke Kawamura, Sahoko Ichihara, Masato Akiyama, Hiroaki Ikezaki, Norihiro Furusyo, Seiko Shimizu, Ken Yamamoto, Makoto Hirata, Rieko Okada, Sayo Kawai, Makoto Kawaguchi, Yuichiro Nishida, Chisato Shimanoe, Rie Ibusuki, Toshiro Takezaki, Mayuko Nakajima, Mikiya Takao, Etsuko Ozaki, Daisuke Matsui, Takeshi Nishiyama, Sadao Suzuki, Naoyuki Takashima, Yoshikuni Kita, Kaori Endoh, Kiyonori Kuriki, Hirokazu Uemura, Kokichi Arisawa, Isao Oze, Keitaro Matsuo, Yohko Nakamura, Haruo Mikami, Takashi Tamura, Hiroshi Nakashima, Takahiro Nakamura, Norihiro Kato, Koichi Matsuda, Yoshinori Murakami, Tatsuaki Matsubara, Mariko Naito, Michiaki Kubo, Yoichiro Kamatani, Nariyoshi Shinomiya, Mitsuhiro Yokota, Kenji Wakai, Yukinori Okada, Hirotaka Matsuo, Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals, Communications Biology, 10.1038/s42003-019-0339-0, 2, 1, 2019.12, Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout..
125. Koji Miura Nishiguchi, Kosuke Fujita, Yasuhiro Ikeda, Hiroshi Kunikata, Yoshito Koyanagi, Masato Akiyama, Toshiaki Abe, Yuko Wada, Koh Hei Sonoda, Toru Nakazawa, A founder Alu insertion in RP1 gene in Japanese patients with retinitis pigmentosa, Japanese Journal of Ophthalmology, 10.1007/s10384-020-00732-5, 2020.01, Purpose: To screen for the 328 bp Alu insertion (c.4052_4053ins328, p.Tyr1352Alafs) in RP1 in a group of retinitis pigmentosa (RP) patients who had been previously identified with a heterozygous deleterious mutation in the gene. Study design: Prospective, clinical and experimental study. Methods: The Alu insertion in RP1 was screened with an optimized PCR-based method in 26 RP patients with a heterozygous deleterious mutation (nonsense or frameshift) in RP1 that had been identified in a preceding genetic study. The genetic location of the previously identified mutation and its inheritance pattern were assessed. Results: Out of 26 RP patients with a heterozygous deleterious mutation in RP1, 5 (19.2%) were found to carry an additional heterozygous Alu insertion, presumably resulting in a compound heterozygous state. This included 3 patients who had been previously diagnosed as autosomal dominant RP based on genetic findings. They were re-diagnosed as having an autosomal recessive disease following our new findings. In all patients identified with the Alu insertion, the other mutations found in the preceding study were outside the defined region in exon 4 (encoding amino acids 677 to 917) in which truncation mutations have been suggested to exert a dominant negative effect. Conclusion: The founder Alu insertion in RP1 is an important cause of autosomal recessive RP in Japanese patients and can be missed in standard targeted resequencing. Screening optimized for this mutation is warranted, particularly in patients with a heterozygous deleterious mutation outside the defined region in exon 4 of RP1..
126. Koji M. Nishiguchi, Hiroshi Kunikata, Kosuke Fujita, Kazuki Hashimoto, Yoshito Koyanagi, Masato Akiyama, Yasuhiro Ikeda, Yukihide Momozawa, Koh Hei Sonoda, Akira Murakami, Yuko Wada, Toru Nakazawa, Association of CRX genotypes and retinal phenotypes confounded by variable expressivity and electronegative electroretinogram, Clinical and Experimental Ophthalmology, 10.1111/ceo.13743, 2020.01, Importance: A framework for understanding the phenotypic features of CRX retinopathy was established. Background: To perform a phenotype-genotype correlation analysis in two groups of patients with heterozygous mutations in distinct locations of the CRX gene, encoding the cone-rod homeobox. Design: Multicentre retrospective study. Participants: Twenty-one Japanese patients from 14 families with a heterozygous CRX mutation. Methods: Retrospective data analysis. Main Outcome Measures: Clinical records on CRX mutation, symptoms, best-corrected visual acuity (BCVA), visual field, fundus photography, fundus auto-fluorescence, optical coherence tomography and electroretinograms (ERGs). Results: Six different CRX heterozygous mutations were identified in the subjects. Twelve patients from 9 families shared the p.R41W mutation and 1 patient had the p.R43C mutation, both of which affect the homeobox domain of CRX. These patients often displayed adult-onset retinal dystrophy with macular degeneration. In contrast, five patients with downstream mutations (p.S204fs, p.S213fs, p.G243X and p.L299F) displayed retinal degeneration or macular degeneration with bone-spicule pigmentation. Three asymptomatic carriers with different mutations (p.R41W, p.S213fs and p.G243X) were present in both groups. Nearly all patients and carriers had an electronegative ERG in response to a bright flash under dark adaptation. There was no cross-sectional association between patients' age and BCVA, despite progressive decline in BCVA. Conclusions and Relevance: Heterozygous mutations within or downstream of the homeobox domain in CRX relate to the difference associated retinal phenotypes, which was confounded by variable expressivity and electronegative ERGs. CRX mutations should be considered in patients with an electronegative ERG with minimal or no macular changes..
127. Tatsuo Masuda, Siew Kee Low, Masato Akiyama, Makoto Hirata, Yutaka Ueda, Koichi Matsuda, Tadashi Kimura, Yoshinori Murakami, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, GWAS of five gynecologic diseases and cross-trait analysis in Japanese, European Journal of Human Genetics, 10.1038/s41431-019-0495-1, 28, 1, 95-107, 2020.01, We performed genome-wide association studies of five gynecologic diseases using data of 46,837 subjects (5236 uterine fibroid, 645 endometriosis, 647 ovarian cancer (OC), 909 uterine endometrial cancer (UEC), and 538 uterine cervical cancer (UCC) cases allowing overlaps, and 39,556 shared female controls) from Biobank Japan Project. We used the population-specific imputation reference panel (n = 3541), yielding 7,645,193 imputed variants. Analyses performed under logistic model, linear mixed model, and model incorporating correlations identified nine significant associations with three gynecologic diseases including four novel findings (rs79219469:C > T, LINC02183, P = 3.3 × 10−8 and rs567534295:C > T, BRCA1, P = 3.1 × 10−8 with OC, rs150806792:C > T, INS-IGF2, P = 4.9 × 10−8 and rs140991990:A > G, SOX9, P = 3.3 × 10−8 with UCC). Random-effect meta-analysis of the five GWASs correcting for the overlapping subjects suggested one novel shared risk locus (rs937380553:A > G, LOC730100, P = 2.0 × 10−8). Reverse regression analysis identified three additional novel associations (rs73494486:C > T, GABBR2, P = 4.8 × 10−8, rs145152209:A > G, SH3GL3/BNC1, P = 3.3 × 10−8, and rs147427629:G > A, LOC107985484, P = 3.8 × 10−8). Estimated heritability ranged from 0.026 for OC to 0.220 for endometriosis. Genetic correlations were relatively strong between OC and UEC, endometriosis and OC, and uterine fibroid and OC (rg > 0.79) compared with relatively weak correlations between UCC and the other four (rg = −0.08 ~ 0.25). We successfully identified genetic associations with gynecologic diseases in the Japanese population. Shared genetic effects among multiple related diseases may help understanding the pathophysiology..
128. Mitsuru Arima, Masato Akiyama, Kohta Fujiwara, Yujiro Mori, Hirosuke Inoue, Eiko Seki, Takahito Nakama, Shoko Tsukamoto, Masayuki Ochiai, Shouichi Ohga, Koh Hei Sonoda, Neurodevelopmental outcomes following intravitreal bevacizumab injection in Japanese preterm infants with type 1 retinopathy of prematurity, PloS one, 10.1371/journal.pone.0230678, 15, 3, 2020.01, Purpose The purpose of this study was to evaluate neurodevelopmental outcomes in 18-month old (corrected age) preterm infants who received an intravitreal bevacizumab (IVB) injection for the treatment of type 1 retinopathy of prematurity (ROP). Methods In this ten-year retrospective study, we reviewed the medical records of patients who underwent ROP screening at Kyushu University Hospital. Among the patients who received IVB or laser photocoagulation (LPC) for the treatment of type 1 ROP, we included infants whose neurodevelopmental examination (the Kyoto Scale of Psychological Development [KSPD]) results at 18 months corrected age were available. Then, the effect of IVB on the developmental quotient (DQ) in each KSPD domain (Postural-Movement, Cognitive-Adaptive, or Language-Social domain) or the overall DQ was investigated by performing linear regression analysis. Results Out of the 513 patients reviewed, 53 were included in the study. IVB and LPC were performed for 14 and 39 patients, respectively. Administration of IVB was significantly associated with neurodevelopmental delay in the Language-Social domain (p = 0.01). The observed association remained even after adjusting for gestational age and birth weight (p = 0.03). Conclusions Administration of IVB may introduce a risk of developmental impairment of interpersonal relationships, socializations, and/or verbal abilities of preterm children. We recommended that preterm infants who received IVB undergo a neurodevelopmental reassessment during their school years or in adulthood..
129. Yoshihiro Kaizu, Shintaro Nakao, Iori Wada, Mitsuru Arima, Muneo Yamaguchi, Keijiro Ishikawa, Masato Akiyama, Junji Kishimoto, Toshio Hisatomi, Koh Hei Sonoda, Microaneurysm Imaging Using Multiple En Face OCT Angiography Image Averaging
Morphology and Visualization, Ophthalmology Retina, 10.1016/j.oret.2019.09.010, 4, 2, 175-186, 2020.02, Purpose: In diabetic retinopathy (DR), OCT angiography (OCTA) could not image all fluorescein angiography (FA)-detected microaneurysms. We investigated whether multiple image averaging could enhance the microaneurysm detection capability of OCTA in patients with DR. Design: Prospective and cross-sectional observational study. Participants: Consecutive 31 patients (n = .62 eyes) with DR. Methods: All eyes underwent FA and 3 × 3 mm fovea-centered OCTA images were obtained using 2 devices: RTVue XR Avanti (Optovue Inc, Fremont, CA) and OCT HS-100 (Canon Inc, Toyko, Japan). OCTA imaging (HS-100) was performed 10 consecutive times. Microaneurysm detection capability was compared among 5 OCTA images (single image, ×3, ×5, and ×10 averaged images and single scan image with the RTVue XR Avanti device). Main Outcome Measures: Microaneurysm detection capability and the correlation between microaneurysm clinical characteristics or morphology and the extent of image averaging required for OCTA detection. Results: A total of 415 microaneurysms could be analyzed in 31 eyes from 25 patients. Microaneurysms detected on single image, ×3, ×5, and ×10 averaged OCTA images were 144 (34.7%), 227 (54.7%), 285 (68.7%), and 306 (73.7%), respectively. Microaneurysm detection capability was significantly increased with increased image averaging. Microaneurysm detection with OCTA was not correlated with retinal thickness, FA leakiness, and indocyanine green angiogram detection or the number of averaged images, whereas there was significant correlation between microaneurysm morphology and microaneurysm visibility by the image-averaging process for 4 morphologies, particular the focal bulge types (P < 0.01). Conclusions: In DR, multiple image averaging is useful for increasing the microaneurysm detection capability of OCTA, especially for focal bulge–type microaneurysms..
130. Saori Sakaue, Jun Hirata, Masahiro Kanai, Ken Suzuki, Masato Akiyama, Chun Lai Too, Thurayya Arayssi, Mohammed Hammoudeh, Samar Al Emadi, Basel K. Masri, Hussein Halabi, Humeira Badsha, Imad W. Uthman, Richa Saxena, Leonid Padyukov, Makoto Hirata, Koichi Matsuda, Yoshinori Murakami, Yoichiro Kamatani, Yukinori Okada, Dimensionality reduction reveals fine-scale structure in the Japanese population with consequences for polygenic risk prediction, Nature communications, 10.1038/s41467-020-15194-z, 11, 1, 2020.03, The diversity in our genome is crucial to understanding the demographic history of worldwide populations. However, we have yet to know whether subtle genetic differences within a population can be disentangled, or whether they have an impact on complex traits. Here we apply dimensionality reduction methods (PCA, t-SNE, PCA-t-SNE, UMAP, and PCA-UMAP) to biobank-derived genomic data of a Japanese population (n = 169,719). Dimensionality reduction reveals fine-scale population structure, conspicuously differentiating adjacent insular subpopulations. We further enluciate the demographic landscape of these Japanese subpopulations using population genetics analyses. Finally, we perform phenome-wide polygenic risk score (PRS) analyses on 67 complex traits. Differences in PRS between the deconvoluted subpopulations are not always concordant with those in the observed phenotypes, suggesting that the PRS differences might reflect biases from the uncorrected structure, in a trait-dependent manner. This study suggests that such an uncorrected structure can be a potential pitfall in the clinical application of PRS..
131. Saori Sakaue, Masato Akiyama, Makoto Hirata, Koichi Matsuda, Yoshinori Murakami, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Functional variants in ADH1B and ALDH2 are non-additively associated with all-cause mortality in Japanese population, European Journal of Human Genetics, 10.1038/s41431-019-0518-y, 28, 3, 378-382, 2020.03, The functional variants involved in alcohol metabolism, the A allele of rs1229984:A > G in ADH1B and the A allele of rs671:G > A in ALDH2, are specifically prevalent among East Asian population. They are shown to be under recent positive selection, but the reasons for the selection are unknown. To test whether these positively selected variants have beneficial effects on survival in modern population, we performed the survival analyses using the large-scale Japanese cohort (n = 135,974) with genotype and follow-up survival data. The rs671-A allele was significantly associated with the better survival in the additive model (HR for mortality = 0.960, P = 1.7 × 10−5), and the rs1229984-A had both additive and non-additive effects (HR = 0.962, P = 0.0016 and HR = 0.958, P = 0.0066, respectively), which was consistent with the positive selection. The favorable effects of these alleles on survival were independent of the habit of alcohol consumption itself. The heterogenous combinatory effect between rs1229984 and rs671 genotype was also observed (HRs for AA genotype at rs671 were 1.03, 0.80, and 0.90 for GG, GA, and AA genotype at rs1229984, respectively), supposedly reflecting the synergistic effects on survival..
132. Keijiro Ishikawa, Ri ichiro Kohno, Kenichiro Mori, Yusuke Murakami, Shintaro Nakao, Masato Akiyama, Shigeo Yoshida, Koh Hei Sonoda, Increased expression of periostin and tenascin-C in eyes with neovascular glaucoma secondary to PDR, Graefe's Archive for Clinical and Experimental Ophthalmology, 10.1007/s00417-019-04574-x, 258, 3, 621-628, 2020.03, Purpose: To investigate periostin (PN) and tenascin-C (TNC) expression in the aqueous humor and trabeculectomy specimens of patients with neovascular glaucoma (NVG) secondary to proliferative diabetic retinopathy (PDR). Methods: This study enrolled 37 eyes of 37 patients who were grouped into (1) NVG secondary to PDR (NVG; n = 8); (2) PDR without NVG (PDR; n = 9); (3) primary open-angle glaucoma (POAG; n = 11); and (4) cataract surgery patients as a control group (CG; n = 9). Aqueous humor samples were collected from the anterior chamber at the start of surgery or intravitreal injection of anti-VEGF drug. The concentrations of PN, TNC, VEGF, and TGF-β2 (transforming growth factor-beta 2) were measured by ELISA. Sclerostomy tissues containing trabecular meshwork were obtained from two NVG patients and a POAG patient who underwent trabeculectomy surgery. Immunohistochemical analyses were performed to determine the localization of PN and TNC expression in the sclerostomy tissues. Results: PN and TNC-C levels were below detection threshold in the POAG and CG groups. The NVG group had significantly higher levels of PN and TNC compared with the PDR group (84.7 ng/ml vs 2.2 ng/ml and 18.5 ng/ml vs 4.6 ng/ml, respectively; p < 0.05). There was a significant correlation between the levels of PN and TNC-C in the NVG group (r = 0.86, p < 0.05). We found significant expression of PN in the trabecular meshwork and Schlemm’s canal of sclerostomy tissues excised from patients with NVG. Conclusions: Increased PN and TNC expression suggests their possible involvement in the pathogenesis of NVG secondary to PDR..
133. Fumihiko Mabuchi, Nakako Mabuchi, Yoichi Sakurada, Seigo Yoneyama, Kenji Kashiwagi, Hiroyuki Iijima, Zentaro Yamagata, Mitsuko Takamoto, Makoto Aihara, Takeshi Iwata, Kazuki Hashimoto, Kota Sato, Yukihiro Shiga, Koji M. Nishiguchi, Toru Nakazawa, Masato Akiyama, Kazuhide Kawase, Mineo Ozaki, Makoto Araie, Genetic Variants Associated With the Onset and Progression of Primary Open-Angle Glaucoma, American journal of ophthalmology, 10.1016/j.ajo.2020.03.014, 215, 135-140, 2020.07, Purpose: We sought to investigate the genetic variants associated with the onset and progression of primary open-angle glaucoma (POAG). Design: Case-control genetic association study. Methods: Japanese POAG patients (n = 505) and control subjects (n = 246) were genotyped for 22 genetic variants predisposing to POAG that can be classified into those associated with intraocular pressure (IOP) elevation (IOP-related genetic variants) and optic nerve vulnerability independent of IOP (non-IOP–related genetic variants). The total number of risk alleles of the 17 IOP-related and 5 non-IOP–related genetic variants were calculated as the genetic risk score (GRS), and the associations between the GRS and family history of glaucoma as an indicator of POAG onset and age at the diagnosis of glaucoma as an indicator of POAG progression were evaluated. Results: There was a significant association (P =.014; odds ratio 1.26 per GRS) between the non-IOP–related GRS, but not IOP-related GRS, and a family history of glaucoma in POAG. As the non-IOP–related GRS increased, the risk of a family history of glaucoma increased. In contrast, a significant association (P =.0014; β = −0.14) was found between the IOP-related GRS, but not non-IOP–related GRS, and age at the diagnosis of glaucoma. As the IOP-related GRS increased, age at the diagnosis of glaucoma decreased. Conclusion: The results indicate that non-IOP–related (optic nerve vulnerability) rather than IOP-related (IOP elevation) genetic variants may play an important role in the onset of POAG (family history of glaucoma) and that IOP-related rather than non-IOP–related genetic variants may play an important role in its progression (age at the diagnosis of glaucoma)..