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

Spracklen, C. N.; Horikoshi, M.; Kim, Y. J.; Lin, K.; Bragg, F.; Moon, S.; Suzuki, K.; Tam, C.; Tabara, Y.; Kwak, S.-H.; Takeuchi, F.; Long, J.; Lim, V.; Chai, J.-F.; Chen, C.-H.; Nakatochi, M.; Yao, J.; Choi, H. S.; Iyengar, A. K.; Perrin, H. J.; Brotman, S. M.; van de Bunt, M.; Gloyn, A. L.; Below, J. L.; Boehnke, M.; Bowden, D. W.; Chambers, J. C.; Mahajan, A.; McCarthy, M. I.; Ng, M. C.; Petty, L. E.; Zhang, W.; Morris, A. P.; Adair, L. S.; Bian, Z.; Chan, J.; Chang, L.-C.; Chee, M.-L.; Chen, Y.-D. I.; Chen, Y.-T.; Chen, Z.; Chuang, L.-M.; Du, S.; Gordon-Larsen, P.; Gross, M.; Guo, X.; Guo

doi:10.1101/685172

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bioRxiv · 10.1101/685172

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

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Abstract

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.\n\nType 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic {beta} cells and insulin resistance in peripheral tissues1. 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 T2D2. 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 another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. 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 circumference5. 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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Spracklen, C. N., Horikoshi, M., Kim, Y. J., Lin, K., Bragg, F., Moon, S., Suzuki, K., Tam, C., Tabara, Y., Kwak, S.-H., Takeuchi, F., Long, J., Lim, V., Chai, J.-F., Chen, C.-H., Nakatochi, M., Yao, J., Choi, H. S., Iyengar, A. K., Perrin, H. J., Brotman, S. M., van de Bunt, M., Gloyn, A. L., Below, J. L., Boehnke, M., Bowden, D. W., Chambers, J. C., Mahajan, A., McCarthy, M. I., Ng, M. C., Petty, L. E., Zhang, W., Morris, A. P., Adair, L. S., Bian, Z., Chan, J., Chang, L.-C., Chee, M.-L., Chen, Y.-D. I., Chen, Y.-T., Chen, Z., Chuang, L.-M., Du, S., Gordon-Larsen, P., Gross, M., Guo, X., Guo. 2019-06-28. Identification of type 2 diabetes loci in 433,540 East Asian individuals. https://doi.org/10.1101/685172

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