Identification of type 2 diabetes loci in 433,540 East Asian individuals

Cassandra N. Spracklen(University of North Carolina at Chapel Hill), Momoko Horikoshi(RIKEN Center for Integrative Medical Sciences), Young Jin Kim(Korea National Institute of Health), Kuang Lin(University of Oxford), Fiona Bragg(University of Oxford), Sanghoon Moon(Korea National Institute of Health), Ken Suzuki(RIKEN Center for Integrative Medical Sciences), Claudia H. T. Tam(Chinese University of Hong Kong), Yasuharu Tabara(Kyoto University), Soo‐Heon Kwak(Seoul National University Hospital), Fumihiko Takeuchi(National Center for Global Health and Medicine), Jirong Long(Vanderbilt University Medical Center), Victor JY Lim(National University of Singapore), Jin Fang Chai(National University of Singapore), Chien-Hsiun Chen(Institute of Biomedical Sciences, Academia Sinica), Masahiro Nakatochi(Nagoya University Hospital), Jie Yao(The Lundquist Institute), Hyeok Sun Choi(Hallym University), Apoorva K. Iyengar(University of North Carolina at Chapel Hill), Hannah J. Perrin(University of North Carolina at Chapel Hill), Sarah M. Brotman(University of North Carolina at Chapel Hill), Martijn van de Bunt(Centre for Human Genetics), Anna L. Gloyn(Centre for Human Genetics), Jennifer E. Below(Vanderbilt University Medical Center), Michael Boehnke(University of Michigan), Donald W. Bowden(Wake Forest University), John C. Chambers(Imperial College Healthcare NHS Trust), Anubha Mahajan(Centre for Human Genetics), Mark I. McCarthy(Centre for Human Genetics), Maggie C. Y. Ng(Wake Forest University), Lauren E. Petty(Vanderbilt University Medical Center), Weihua Zhang(Ealing Hospital), Andrew P. Morris(Centre for Human Genetics), Linda S. Adair(University of North Carolina at Chapel Hill), Zheng Bian(Chinese Academy of Medical Sciences & Peking Union Medical College), Juliana C.N. Chan(Chinese University of Hong Kong), Li-Ching Chang(Institute of Biomedical Sciences, Academia Sinica), Miao-Li Chee(Singapore National Eye Center), Yii‐Der Ida Chen(The Lundquist Institute), Yuan-Tsong Chen(The Lundquist Institute), Zhengming Chen(University of Oxford), Lee‐Ming Chuang(National Taiwan University), Shufa Du(University of North Carolina at Chapel Hill), Penny Gordon‐Larsen(University of North Carolina at Chapel Hill), Myron D. Gross(University of Minnesota), Xiuqing Guo(The Lundquist Institute), Canqing Yu(Chinese Academy of Medical Sciences & Peking Union Medical College), Sohee Han(Korea National Institute of Health), Annie-Green Howard(University of North Carolina at Chapel Hill), Wei Huang(Chinese National Human Genome Center), Yi‐Jen Hung(Tri-Service General Hospital Songshan Branch), Mi Yeong Hwang(Korea National Institute of Health), Chii‐Min Hwu(National Yang Ming Chiao Tung University), Sahoko Ichihara(Jichi Medical University), Masato Isono(National Center for Global Health and Medicine), Hye-Mi Jang(Korea National Institute of Health), Guozhi Jiang(Chinese University of Hong Kong), Jost B. Jonas(Heidelberg University), Yoichiro Kamatani(RIKEN Center for Integrative Medical Sciences), Tomohiro Katsuya(The University of Osaka), Takahisa Kawaguchi(Kyoto University), Chiea Chuen Khor(Agency for Science, Technology and Research), Katsuhiko Kohara(Ehime University), Myung‐Shik Lee(Yonsei University), Nannette R Lee(University of San Carlos), Liming Li(Peking University), Jianjun Liu(Agency for Science, Technology and Research), Andrea O. Y. Luk(Chinese University of Hong Kong), Jun Lv(Peking University), Yukinori Okada(The University of Osaka), Mark A. Pereira(University of Minnesota), Charumathi Sabanayagam(National University of Singapore), Jinxiu Shi(Chinese National Human Genome Center), Dong Mun Shin(Korea National Institute of Health), Wing Yee So(Chinese University of Hong Kong), Atsushi Takahashi(National Cerebral and Cardiovascular Center), Brian Tomlinson(Chinese University of Hong Kong), Fuu‐Jen Tsai(China Medical University), Rob M. van Dam(Harvard University), Yong‐Bing Xiang(Renji Hospital), Ken Yamamoto(Kurume University Medical Center), Toshimasa Yamauchi(The University of Tokyo), Kyungheon Yoon(Korea National Institute of Health), Canqing Yu(Peking University), Jian‐Min Yuan(University of Pittsburgh), Liang Zhang(Singapore National Eye Center), Wei Zheng(Vanderbilt University Medical Center), Michiya Igase(Ehime University), Yoon Shin Cho(Hallym University), Jerome I. Rotter(The Lundquist Institute), Ya Xing Wang(Beijing Tongren Hospital), Wayne Huey‐Herng Sheu(National Yang Ming Chiao Tung University), Mitsuhiro Yokota(Kurume University), Jer‐Yuarn Wu(Institute of Biomedical Sciences, Academia Sinica), Ching‐Yu Cheng(National University of Singapore), Tien Yin Wong(National University of Singapore), Xiao‐Ou Shu(Vanderbilt University Medical Center), Norihiro Kato(National Center for Global Health and Medicine), Kyong Soo Park(Seoul National University), E Shyong Tai(National University of Singapore), Fumihiko Matsuda(Kyoto University), Woon‐Puay Koh(National University of Singapore), Ronald C.W.(Chinese University of Hong Kong), Shiro Maeda(University of the Ryukyus), Iona Y. Millwood(University of Oxford), Juyoung Lee(Korea National Institute of Health), Takashi Kadowaki(The University of Tokyo), Robin Walters(University of Oxford), Bong-Jo Kim(Korea National Institute of Health), Karen L. Mohlke(University of North Carolina at Chapel Hill), Xueling Sim(National University of Singapore)
bioRxiv (Cold Spring Harbor Laboratory)
June 28, 2019
10.1101/685172
Cited by 61Open Access
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Abstract

SUMMARY Meta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1 , PTF1A , SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1 , in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways. Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues 1 . Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D 2 . Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another 3,4 . Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci 4 . The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference 5 . We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

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