Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Accession codes


Gene Expression Omnibus


  1. Parikh, N.I. et al. Increasing trends in incidence of overweight and obesity over 5 decades. Am. J. Med. 120, 242–250 (2007).

    Article  Google Scholar 

  2. Ogden, C.L. et al. Prevalence of overweight and obesity in the United States, 1999–2004. J. Am. Med. Assoc. 295, 1549–1555 (2006).

    Article  CAS  Google Scholar 

  3. Haslam, D.W. & James, W.P. Obesity. Lancet 366, 1197–1209 (2005).

    Article  Google Scholar 

  4. Wardle, J., Carnell, S., Haworth, C.M. & Plomin, R. Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. Am. J. Clin. Nutr. 87, 398–404 (2008).

    Article  CAS  Google Scholar 

  5. Maes, H.H., Neale, M.C. & Eaves, L.J. Genetic and environmental factors in relative body weight and human adiposity. Behav. Genet. 27, 325–351 (1997).

    Article  CAS  Google Scholar 

  6. Rankinen, T. et al. The human obesity gene map: the 2005 update. Obesity (Silver Spring) 14, 529–644 (2006).

    Article  Google Scholar 

  7. Mutch, D.M. & Clement, K. Unraveling the genetics of human obesity. PLoS Genet. 2, e188 (2006).

    Article  Google Scholar 

  8. Gudbjartsson, D.F. et al. Many sequence variants affecting diversity of adult human height. Nat. Genet. 40, 609–615 (2008).

    Article  CAS  Google Scholar 

  9. Frayling, T.M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

    Article  CAS  Google Scholar 

  10. Loos, R.J. et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat. Genet. 40, 768–775 (2008).

    Article  CAS  Google Scholar 

  11. Chambers, J.C. et al. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat. Genet. 40, 716–718 (2008).

    Article  CAS  Google Scholar 

  12. Saxena, R. et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).

    Article  CAS  Google Scholar 

  13. International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  14. Willer, C.J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. advance online publication, doi:10.1038/ng.287 (14 December 2008).

  15. Jurvansuu, J. et al. Transmembrane protein 18 enhances the tropism of neural stem cells for glioma cells. Cancer Res. 68, 4614–4622 (2008).

    Article  CAS  Google Scholar 

  16. Jamshidi, Y., Snieder, H., Ge, D., Spector, T.D. & O'Dell, S.D. The SH2B gene is associated with serum leptin and body fat in normal female twins. Obesity (Silver Spring) 15, 5–9 (2007).

    Article  CAS  Google Scholar 

  17. Chouchane, L. et al. Genetic variation in the stress protein hsp70–2 gene is highly associated with obesity. Int. J. Obes. Relat. Metab. Disord. 25, 462–466 (2001).

    Article  CAS  Google Scholar 

  18. Hamid, Y.H. et al. The common T60N polymorphism of the lymphotoxin-alpha gene is associated with type 2 diabetes and other phenotypes of the metabolic syndrome. Diabetologia 48, 445–451 (2005).

    Article  CAS  Google Scholar 

  19. Sookoian, S.C., Gonzalez, C. & Pirola, C.J. Meta-analysis on the G-308A tumor necrosis factor alpha gene variant and phenotypes associated with the metabolic syndrome. Obes. Res. 13, 2122–2131 (2005).

    Article  Google Scholar 

  20. Willer, C.J. et al. Screening of 134 single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes. Diabetes 56, 256–264 (2007).

    Article  CAS  Google Scholar 

  21. Gratacos, M. et al. Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol. Psychiatry 61, 911–922 (2007).

    Article  CAS  Google Scholar 

  22. Gunstad, J. et al. BDNF Val66Met polymorphism is associated with body mass index in healthy adults. Neuropsychobiology 53, 153–156 (2006).

    Article  CAS  Google Scholar 

  23. Aravind, L. & Koonin, E.V. Fold prediction and evolutionary analysis of the POZ domain: structural and evolutionary relationship with the potassium channel tetramerization domain. J. Mol. Biol. 285, 1353–1361 (1999).

    Article  CAS  Google Scholar 

  24. Ding, X.F. et al. Characterization and expression of a human KCTD1 gene containing the BTB domain, which mediates transcriptional repression and homomeric interactions. DNA Cell Biol. 27, 257–265 (2008).

    Article  CAS  Google Scholar 

  25. Marg, A. et al. Neurotractin, a novel neurite outgrowth-promoting Ig-like protein that interacts with CEPU-1 and LAMP. J. Cell Biol. 145, 865–876 (1999).

    Article  CAS  Google Scholar 

  26. Schafer, M., Brauer, A.U., Savaskan, N.E., Rathjen, F.G. & Brummendorf, T. Neurotractin/kilon promotes neurite outgrowth and is expressed on reactive astrocytes after entorhinal cortex lesion. Mol. Cell. Neurosci. 29, 580–590 (2005).

    Article  Google Scholar 

  27. Mi, H. et al. The PANTHER database of protein families, subfamilies, functions and pathways. Nucleic Acids Res. 33, D284–D288 (2005).

    Article  CAS  Google Scholar 

  28. Gullicksen, P.S., Della-Fera, M.A. & Baile, C.A. Leptin-induced adipose apoptosis: Implications for body weight regulation. Apoptosis 8, 327–335 (2003).

    Article  CAS  Google Scholar 

  29. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

    Article  CAS  Google Scholar 

  30. Steinthorsdottir, V. et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat. Genet. 39, 770–775 (2007).

    Article  CAS  Google Scholar 

  31. Gulcher, J.R., Kristjansson, K., Gudbjartsson, H. & Stefansson, K. Protection of privacy by third-party encryption in genetic research in Iceland. Eur. J. Hum. Genet. 8, 739–742 (2000).

    Article  CAS  Google Scholar 

  32. Jorgensen, T. et al. A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99. Eur. J. Cardiovasc. Prev. Rehabil. 10, 377–386 (2003).

    Article  Google Scholar 

  33. Lauritzen, T. et al. The ADDITION study: proposed trial of the cost-effectiveness of an intensive multifactorial intervention on morbidity and mortality among people with Type 2 diabetes detected by screening. Int. J. Obes. Relat. Metab. Disord. 24, Suppl 3, S6–S11 (2000).

    Article  Google Scholar 

  34. Kutyavin, I.V. et al. A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res. 34, e128 (2006).

    Article  Google Scholar 

  35. Devlin, B., Bacanu, S.A. & Roeder, K. Genomic Control to the extreme. Nat. Genet. 36, 1129–1130 (2004).

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Corresponding authors

Correspondence to Gudmar Thorleifsson or Kari Stefansson.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing