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Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

Abstract

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of an association with T2D for PEPD5 and HNF4A6,7 has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.

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Figure 1: Genome-wide Manhattan plot for the east Asian T2D stage 1 meta-analysis.
Figure 2: Regional association plots for new T2D loci.

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Acknowledgements

We thank all the participants and the staff of the BioBank Japan project. The project was supported by a grant from the Leading Project of Ministry of Education, Culture, Sports, Science and Technology Japan.

The Japan Cardiometabolic Genome Epidemiology (CAGE) Network Studies were supported by grants for the Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); the Core Research for Evolutional Science and Technology (CREST) from the Japan Science Technology Agency; the Grant of National Center for Global Health and Medicine (NCGM).

We thank the Office of Population Studies Foundation research and data collection teams for the Cebu Longitudinal Health and Nutrition Survey. This work was supported by US National Institutes of Health grants DK078150, TW05596, HL085144 and TW008288 and pilot funds from grants RR20649, ES10126, and DK56350.

We acknowledge support from the Hong Kong Government Research Grants Council Central Allocation Scheme (CUHK 1/04C), Research Grants Council Earmarked Research Grant (CUHK4724/07M) and the Innovation and Technology Fund of the Government of the Hong Kong Special Administrative Region (ITS/487/09FP). We acknowledge the Chinese University of Hong Kong Information Technology Services Center for support of computing resources. We would also like to thank the dedicated medical and nursing staff at the Prince of Wales Hospital Diabetes and Endocrine Centre.

This work was supported by grants from Korea Centers for Disease Control and Prevention (4845-301, 4851-302, 4851-307) and an intramural grant from the Korea National Institute of Health (2011-N73005-00), the Republic of Korea.

The work by the National Taiwan University Hospital was supported in part by the grant (NSC99-3112-B-002-019) from the National Science Council of Taiwan. We would also like to acknowledge the National Genotyping Center of National Research Program for Genomic Medicine (NSC98-3112-B-001-037), Taiwan.

The work by the Shanghai Diabetes Genetic Study was supported in part by the US National Institutes of Health grants R01CA124558, R01CA64277, R01CA70867, R01CA90899, R01CA100374, R01CA118229, R01CA92585, UL1 RR024975, DK58845 and HG004399, the Department of Defense Idea Award BC050791, Vanderbilt Ingram professorship funds and the Allen Foundation Fund. We thank the dedicated investigators and staff members from research teams at Vanderbilt University, Shanghai Cancer Institute and the Shanghai Institute of Preventive Medicine, and especially, the study participants for their contributions in the studies.

The work of the Shanghai Diabetes Study was supported by grants from the National 973 Program (2011CB504001), the Project of National Natural Science Foundation of China (30800617) and the Shanghai Rising-Star Program (09QA1404400), China.

The work of the Shanghai Jiao Tong University Diabetes Study was supported by grants from the National 863 Program (2006AA02A409) and the major program of the Shanghai Municipality for Basic Research (08dj1400601), China.

The work of the Seoul National University Hospital was supported by grants from the Korea Health 21 R&D Project, Ministry of Health & Welfare (00-PJ3-PG6-GN07-001) and the World Class University project of the Ministry of Education, Science and Technology (MEST) and National Research Foundation (NRF) (R31-2008-000-10103-0), Korea. The Singapore Prospective Study Program (SP2) was funded through grants from the Biomedical Research Council of Singapore (BMRC05/1/36/19/413 and 03/1/27/18/216) and the National Medical Research Council of Singapore (NMRC/1174/2008). E.S.T. also receives additional support from the National Medical Research Council through a clinicians scientist award (NMRC/CSA/008/2009). The Singapore Malay Eye Study (SiMES) was funded by the National Medical Research Council (NMRC0796/2003 and NMRC/STaR/0003/2008) and Biomedical Research Council (BMRC, 09/1/35/19/616). Y.Y.T. acknowledges support from the Singapore National Research Foundation, NRF-RF-2010-05. The Genome Institute of Singapore carried out all the genotyping for the samples from Singapore also provided funding for the genotyping of the samples from SP2.

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The study was supervised by E.S.T., B.-G.H., N.K., Y.S.C., Y.Y.T., W.Z., Q.C., X.O.S., Y.-T.C., J.-Y.W., L.S.A., K.L.M., T.K., C.H., W.J., L.-M.C., Y.M.C., K.S.P., J.-Y.L. and J.C.N.C. The experiments were conceived of and designed by Y.S.C., E.S.T., N.K., D.P.-K.N., J.J.-M.L., M.S., T.Y.W., Y.Y.T., W.Z., F.B.H., X.O.S., C.-H.C., F.-J.T., Y.-T.C., J.-Y.W., L.S.A., K.L.M., S.M., C.H., L.-M.C., K.S.P., M.J.G., M.I.M. and R.C.W.M. The experiments were performed by J.L., M.S., J.J.L., J.-Y.W., S.M., R.Z., K.Y., Y.-C.C., T.-J.C., L.-M.C. and S.H.K. Statistical analyses was performed by M.J.G., X.S., Y.J.K., R.T.H.O., W.T.T., Y.Y.T., F.T., J.L., C.-H.C., L.-C.C., Y.W., Y.L., K.H., C.H., Y.-C.C., S.H.K., A.P.M. and R.C.W.M. The data were analyzed by M.J.G., X.S., Y.J.K., R.T.H.O., W.T.T., Y.Y.T., J.L., C.-H.C., L.-C.C., Y.W., N.R.L., Y.L., L.S.A., K.L.M., T.Y., C.H., Y.-C.C., S.H.K., Y.S.C., S.K., Å.K.H. and R.C.W.M. The reagents, materials and analysis tools were contributed by E.S.T., B.-G.H., N.K., D.P.-K.N., J.J.-M.L., J.L., M.S., T.A., T.Y.W., E.N., M.Y., J.N., J.J.L., W.Z., Q.C., Y.G., W.L., F.B.H., X.O.S., F.-J.T., Y.-T.C., J.-Y.W., N.R.L., Y.L., K.O., H.I., R.T., C.W., Y.B., T.-J.C., L.-M.C., K.S.P., H.-L.K., N.H.C., J.-Y.L., W.Y.S. and J.C.N.C. The manuscript was written by Y.S.C., M.S. and E.S.T. All authors reviewed the manuscript.

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Correspondence to Yoon Shin Cho, E Shyong Tai or Mark Seielstad.

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A list of full members is provided in the Supplementary Note.

A list of full members is provided in the Supplementary Note.

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Cho, Y., Chen, CH., Hu, C. et al. Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nat Genet 44, 67–72 (2012). https://doi.org/10.1038/ng.1019

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