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Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity

Abstract

Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 × 10−7. This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.

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Acknowledgements

The authors would like to thank all of the study participants and clinical collaborators for their cooperation. We would also like to acknowledge the staff at the Clinical Research Centre (Iceland) and the deCODE Genetics biological materials and genotyping facilities for their work. The research performed at deCODE Genetics was part funded through the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413. deCODE Genetics would like to thank the GIANT Consortium for their cooperation and in particular J.N. Hirschhorn, M.I. McCarthy, C.M. Lindgren, J.C. Randall and S. Li for providing genome wide association results for the BMI and weight analysis. The US data collection was supported by grants HL072518 and HL087698 from the National Institutes of Health, the Johns Hopkins General Clinical Research Center, the National Center for Research Resources (M01-RR000052), and the National Institutes of Health. The Danish study was supported by grants from the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care (LUCAMP) and the Danish Health Research Council.

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G.T., G.B.W., U.T. and K.S. wrote the first draft of the paper. G.B.W., V.S., A.H., U.S., S.G., S.T., I.J., E.J.O., G.H.O., T. Jonsson, L.T. and T.R. participated in the collection of the Icelandic data. K.B.-J., T.H., G.A., T. Jorgensen, T.L. and O.P. recruited and phenotyped the Danish study samples. K.K.A., A.L.M.V., N.R., E.K. and L.A.K. collected the Dutch data. D.M.B., L.R.Y. and L.C.B. collected the US data. G.T., G.B.W., D.F.G. and P.S. analyzed the data. G.B.W., T. Jonsdottir and F.J. carried out the genotyping. G.T., G.B.W., J.G., A.K., U.T. and K.S. planned and supervised the work. All authors contributed to the final version of the paper.

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Correspondence to Gudmar Thorleifsson or Kari Stefansson.

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Some of the authors are employed by deCODE Genetics and own stock or stock options in the company.

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Supplementary Methods, Supplementary Note, Supplementary Tables 1–14 and Supplementary Figure 1 (PDF 1352 kb)

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Thorleifsson, G., Walters, G., Gudbjartsson, D. et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 41, 18–24 (2009). https://doi.org/10.1038/ng.274

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