Abstract
Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 × 10−8), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated with BMI with P < 5.0 × 10−7. Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations.
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Acknowledgements
The Shanghai Genome Wide Associations Studies (SGWAS) would like to thank the dedicated investigators and staff members from the research teams at Vanderbilt University, the Shanghai Cancer Institute and the Shanghai Institute of Preventive Medicine and, most of all, the study participants for their contributions to this work. Genotyping assays and statistical analyses for the SGWAS were primarily supported by grants from the US National Institutes of Health (NIH; R01 CA064277, R37 CA070867, R01 CA090899, R01 CA118229, R01 CA092585 and R01 CA122756), as well as by Ingram professorship funds, Allen Foundation funds and a Vanderbilt Clinical and Translational Science Award (CTSA; 1 UL1 RR024975) from the National Center for Research Resources (NCRR) at the NIH. NIH grants provided support for the participating studies, including the Shanghai Breast Cancer Study (R01 CA064277), the Shanghai Breast Cancer Survival Study (R01 CA118229) and the Shanghai Endometrial Cancer Study (R01 CA092585). The KARE project was supported by grants from the Korea Centers for Disease Control and Prevention (4845-301, 4851-302 and 4851-307). The Singapore Prospective Study Program (SP2) was funded through grants from the Biomedical Research Council of Singapore (BMRC; 05/1/36/19/413 and 03/1/27/18/216) and the National Medical Research Council of Singapore (NMRC; NMRC/1174/2008). E.S.T. also received support from the NMRC through a clinician scientist award (NMRC/CSA/008/2009). The Singapore Malay Eye Study (SiMES) was funded by the NMRC (NMRC/0796/2003 and NMRC/STaR/0003/2008) and the BMRC (09/1/35/19/616). The CAGE Network Studies were supported by grants for the Core Research for Evolutional Science and Technology (CREST) from the Japan Science Technology Agency, the Program for Promotion of Fundamental Studies in Health Sciences, the National Institute of Biomedical Innovation Organization (NIBIO) and the National Center for Global Health and Medicine (NCGM). L.Q. is supported by a grant from the NIH (HL071981), an American Heart Association Scientist Development Award and the Boston Obesity Nutrition Research Center (DK46200). The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) is supported by research grants from the National Heart, Lung, and Blood Institute at the NIH (HL072507, HL087263 and HL090682). SINDI was funded by grants from the BMRC (09/1/35/19/616 and 08/1/35/19/550) and the NMRC (NMRC/STaR/0003/2008). SCORM was funded by the NMRC (NMRC/0975/2005), the BMRC (06/1/21/19/466) and the Centre for Molecular Epidemiology at the National University of Singapore. The SIH was supported by the Chinese National Key Program for Basic Research (973:2004CB518603) and the Chinese National High Tech Program (863:2009AA022703). The MEC was supported by grants from the National Cancer Institute (NCI; CA063464, CA054281 and CA132839) and from the NIH Genes, Environment and Health Initiative (GEI; HG004726). Assistance with genotype cleaning for the MEC Japanese prostate cancer study was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Funding support for genotyping, which was performed at the Broad Institute of MIT and Harvard University, was provided by the GEI (HG04424).
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T.A., Y.-S.C., Y.-T.G., D.G., B.-G.H., J.H., F.B.H., N. Kamatani, N. Kato, L.-L.-M., J.-Y.L., W.L., Z.M., Y.N., D.P.-K.N., L.Q., S.-M.S., X.-O.S., E.-S.T., F.-J.T., T. Tanaka, F.J.T., T.-Y.W., J.-Y.W., Y.-B.X., J.X., W.Z. and D.Z. supervised the research. Y.-S.C., D.G., J.H., Y.H., N. Kato, J. Liang, Z.M., Y.N., L.Q., M.S., X.-O.S., H.S., E.S.T., T. Tanaka, T.-Y.W., W.Z. and D.Z. conceived and designed the experiments. J.H., Y.H., M.K., J. Liang, M.S., J.S., M.Y. and Y.Z. performed the experiments. L.-C.C., C.-H.C., G.K.C., R.D., M.-J.G., M.H., Y.H., C.L., J. Long, Y.O., L.Q., M.-H.S., Y.T., A.T., T. Tsunoda and W.W. performed the statistical analyses. The GIANT Consortium, Q.C., L.-C.C., C.-H.C., R.J.D., R.D., M.-J.G., M.H., Y.H., N.I., J. Long, T.M., Y.O., R.T.H.O., L.Q., X.S., M.-H.S. and Y.T. analyzed the data. T.A., Q.C., Y.-T.G., C.A.H., B.E.H., N.I., N. Kato, Y.K., L.L.-M., J. Liang, J.-J.L., W.L., D.P.-K.N., L.Q., S.-M.S., M.S., X.-O.S., H.S., E.S.T., F.-J.T., T.-Y.W., J.-Y.W., Y.-B.X., K.Y., M.Y., C.S.J.F. and W.Z. contributed reagents, materials and/or analysis tools. R.J.D., Y.O., X.-O.S., E.S.T., T. Tanaka, W.W. and W.Z. wrote the manuscript. S.M. reviewed the manuscript for important intellectual content. All authors reviewed and approved the final version of the manuscript.
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Wen, W., Cho, YS., Zheng, W. et al. Meta-analysis identifies common variants associated with body mass index in east Asians. Nat Genet 44, 307–311 (2012). https://doi.org/10.1038/ng.1087
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DOI: https://doi.org/10.1038/ng.1087