Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation.
Chu AY., Deng X., Fisher VA., Drong A., Zhang Y., Feitosa MF., Liu CT., Weeks O., Choh AC., Duan Q., Dyer TD., Eicher JD., Guo X., Heard-Costa NL., Kacprowski T., Kent JW., Lange LA., Liu X., Lohman K., Lu L., Mahajan A., O'Connell JR., Parihar A., Peralta JM., Smith AV., Zhang Y., Homuth G., Kissebah AH., Kullberg J., Laqua R., Launer LJ., Nauck M., Olivier M., Peyser PA., Terry JG., Wojczynski MK., Yao J., Bielak LF., Blangero J., Borecki IB., Bowden DW., Carr JJ., Czerwinski SA., Ding J., Friedrich N., Gudnason V., Harris TB., Ingelsson E., Johnson AD., Kardia SL., Langefeld CD., Lind L., Liu Y., Mitchell BD., Morris AP., Mosley TH., Rotter JI., Shuldiner AR., Towne B., Völzke H., Wallaschofski H., Wilson JG., Allison M., Lindgren CM., Goessling W., Cupples LA., Steinhauser ML., Fox CS.
Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10(-8); false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.