Genome-Wide Study of Subcutaneous and Visceral Adipose Tissue Reveals Novel Sex-Specific Adiposity Loci in Mexican Americans

Objective This study aimed to explore genetic mechanisms of regional fat deposition, which is a strong risk factor for metabolic diseases beyond total adiposity. Methods A genome-wide association study of 7,757,139 SNPs in 983 Mexican Americans (Nmale=403, Nfemale=580) from the Insulin Resistance Atherosclerosis Family Study (IRASFS) was performed. Association analyses were performed with and without sex stratification for subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and visceral-subcutaneous ratio (VSR) obtained from computed tomography (CT). Results The strongest signal identified was SNP rs2185405 (MAF=40%, PVAT=1.98×10-8) with VAT. It is an intronic variant of the GLIS family zinc finger 3 gene (GLIS3). In addition, SNP rs12657394 (MAF=19%) was associated with VAT in males (Pmale=2.39×10-8; Pfemale=2.5×10-3). It is located intronically in the serum response factor binding protein 1 gene (SRFBP1). On average, male carriers of the variant had 24.6cm2 increased VAT compared to non-carriers. Subsequently, genome-wide SNP-sex interaction analysis was performed. SNP rs10913233 (MAF=14%, Pint=3.07×10-8) in PAPPA2 and rs10923724 (MAF=38%, Pint=2.89×10-8) upstream of TBX15 were strongly associated with the interaction effect for VSR. Conclusions Six loci were identified with genome-wide significant associations with fat deposition and interactive effects. These results provided genetic evidence for a differential basis of fat deposition between genders.