Yoneyama S, Guo Y, Lanktree MB, Barnes MR, Elbers CC, Karczewski KJ, Padmanabhan S, Bauer F, Baumert J, Beitelshees A, Berenson GS, Boer JM, Burke G, Cade B, Chen W, Cooper-Dehoff RM, Gaunt TR, Gieger C, Gong Y, Gorski M, Heard-Costa N, Johnson T, Lamonte MJ, McDonough C, Monda KL, Onland-Moret NC, Nelson CP, O'Connell JR, Ordovas J, Peter I, Peters A, Shaffer J, Shen H, Smith E, Speilotes L, Thomas F, Thorand B, Monique Verschuren WM, Anand SS, Dominiczak A, Davidson KW, Hegele RA, Heid I, Hofker MH, Huggins GS, Illig T, Johnson JA, Kirkland S, Look AHEAD Research Group, König W, Langaee TY, McCaffery J, Melander O, Mitchell BD, Munroe P, Murray SS, Papanicolaou G, Redline S, Reilly M, Samani NJ, Schork NJ, Van Der Schouw YT, Shimbo D, Shuldiner AR, Tobin MD, Wijmenga C, Yusuf S, GIANT Consortium, CARe IBC Consortium, Hakonarson H, Lange LA, Demerath EW, Fox CS, North KE, Reiner AP, Keating B, Taylor KC
Gene-centric Meta-analyses for Central Adiposity Traits in Up to 57 412 Individuals of European Descent Confirm Known Loci and Reveal Several Novel Associations.
Human Molecular Genetics. 2014 May 01; 23: 2498-510.
Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ?50 000 cosmopolitan tagged SNPs across ?2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (? ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (? = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (? = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (? = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (? = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.