Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
At a glance
- Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women. The Nurses' Health Study. Am. J. Epidemiol. 145, 614–619 (1997). et al.
- Comparison of abdominal adiposity and overall obesity in predicting risk of type 2 diabetes among men. Am. J. Clin. Nutr. 81, 555–563 (2005). , , , &
- Distribution of body fat and risk of coronary heart disease in men and women. Curr. Opin. Cardiol. 23, 591–598 (2008).
- General and abdominal adiposity and risk of death in Europe. N. Engl. J. Med. 359, 2105–2120 (2008). et al.
- Associations of hip and thigh circumferences independent of waist circumference with the incidence of type 2 diabetes: the Hoorn Study. Am. J. Clin. Nutr. 77, 1192–1197 (2003). et al.
- Trunk fat and leg fat have independent and opposite associations with fasting and postload glucose levels: the Hoorn study. Diabetes Care 27, 372–377 (2004). et al.
- Heritability estimates for beta cell function and features of the insulin resistance syndrome in UK families with an increased susceptibility to type 2 diabetes. Diabetologia 47, 732–738 (2004). et al.
- Anthropometry, carbohydrate and lipid metabolism in the East Flanders Prospective Twin Survey: heritabilities. Diabetologia 50, 2107–2116 (2007). et al.
- Genetic and behavioral determinants of waist-hip ratio and waist circumference in women twins. Obes. Res. 6, 383–392 (1998). , , &
- Genetic and behavioral influences on body fat distribution. Int. J. Obes. 14, 593–602 (1990). et al.
- Genetic disorders of adipose tissue development, differentiation, and death. Annu. Rev. Genomics Hum. Genet. 7, 175–199 (2006). &
- Acquired and inherited lipodystrophies. N. Engl. J. Med. 350, 1220–1234 (2004).
- Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet. 5, e1000508 (2009). et al.
- Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat. Genet. 41, 18–24 (2009). et al.
- Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009). et al.
- Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat. Genet. 40, 768–775 (2008). et al.
- Sex-specific genetic effects influence variation in body composition. Diabetologia 51, 2233–2241 (2008). 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). et al.
- Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 41, 56–65 (2009). et al.
- New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010). et al.
- Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat. Genet. 42, 142–148 (2010). et al.
- Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 5, e1000534 (2009). et al.
- PANTHER: a library of protein families and subfamilies indexed by function. Genome Res. 13, 2129–2141 (2003). et al.
- Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463, 666–670 (2010). et al.
- A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 463, 671–675 (2010). et al.
- Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010). et al.
- Wellcome Trust Case Control Consortium. et al. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464, 713–720 (2010).
- Predicting tissue-specific enhancers in the human genome. Genome Res. 17, 201–211 (2007). , , &
- Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008). et al.
- Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008). et al.
- A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007). et al.
- Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. advance online publication, doi:10.1038/ng.686 (10 October 2010). et al.
- Sexual dimorphism of body composition. Best Pract. Res. Clin. Endocrinol. Metab. 21, 415–430 (2007).
- Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat. Genet. 41, 47–55 (2009). et al.
- SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat. Genet. 40, 430–436 (2008). et al.
- Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet. 4, e28 (2008). et al.
- Polymorphism in the CETP gene region, HDL cholesterol, and risk of future myocardial infarction: genomewide analysis among 18,245 initially healthy women from the Women's Genome Health Study. Circ. Cardiovasc. Genet. 2, 26–33 (2009). et al.
- Improved glucose homeostasis and enhanced insulin signalling in Grb14-deficient mice. EMBO J. 23, 582–593 (2004). et al.
- Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat. Genet. 40, 638–645 (2008). et al.
- Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010). et al.
- Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients–EUGENE2 study. PLoS ONE 4, e7236 (2009). et al.
- Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels. Diabetes 56, 1517–1526 (2007). et al.
- Angiogenic factors are elevated in overweight and obese individuals. Int. J. Obes. (Lond) 29, 1308–1314 (2005). , , &
- Effects of weight loss after bariatric surgery for morbid obesity on vascular endothelial growth factor-A, adipocytokines, and insulin. J. Clin. Endocrinol. Metab. 93, 4276–4281 (2008). et al.
- Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc. Natl. Acad. Sci. USA 103, 6676–6681 (2006). et al.
- Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007). , &
- Positioning of the mouse Hox gene clusters in the nuclei of developing embryos and differentiating embryoid bodies. Exp. Cell Res. 313, 1449–1459 (2007). , &
- Dorsoventral patterning of the mouse coat by Tbx15. PLoS Biol. 2, E3 (2004). et al.
- Human genetics illuminates the paths to metabolic disease. Nature 462, 307–314 (2009).
- Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution. J. Clin. Invest. 72, 1150–1162 (1983). , , &
- Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 116, 39–48 (2007). et al.
- Simple anthropometric measures correlate with metabolic risk indicators as strongly as magnetic resonance imaging-measured adipose tissue depots in both HIV-infected and control subjects. Am. J. Clin. Nutr. 87, 1809–1817 (2008). et al.
- Influence of body fat content and distribution on variation in metabolic risk. J. Clin. Endocrinol. Metab. 91, 4459–4466 (2006). et al.
- Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009). , , &
- A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007). , , , &
- Imputation-based analysis of association studies: candidate regions and quantitative traits. PLoS Genet. 3, e114 (2007). &
- Theoretical Statistics (Chapman and Hall, London, 1979). &
- Genomic control for association studies. Biometrics 55, 997–1004 (1999). &
- Adjustment During Army Life (Princeton University Press, Princeton, New Jersey, USA, 1949). , , , &
- Combining probability from independent tests: the weighted Z-method is superior to Fisher's approach. J. Evol. Biol. 18, 1368–1373 (2005).
- Controlling the false discovery rate–a practical and powerful approach to multiple testing. J. R. Stat. Soc. Series B Stat. Methodol. 57, 289–300 (1995). &