Genome-wide study of subcutaneous and visceral adipose tissue reveals novel sex-specific adiposity loci in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study

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 (N(male)=403, N(female)=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%, P(VAT)=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 (P(male)=2.39×10(-8); P(female)=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 24.6cm(2) increased VAT compared to non-carriers. Subsequently, genome-wide SNP-sex interaction analysis was performed. SNP rs10913233 (MAF=14%, P(int)=3.07×10(-8)) in PAPPA2 and rs10923724 (MAF=38%, P(int)=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.