Genome-wide association of body fat distribution in African ancestry populations suggests new loci

Abstract

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

Trial registration: ClinicalTrials.gov NCT00005267.

Figure 1. Regional association plots based on single GC-corrected p-value for LHX2 and RREB1, Stage 1 only.

MAF = minor allele frequency. The p-values for the index SNP rs2075064 in LHX2 loci are 5.5E-8, 0.03, and 2.2E-8 for Stage 1, Stage 2 and joint analysis. The p-values for the index SNP rs6931262 at RREB1 loci are 5.3E-8, 0.02 and 2.5E-8 for Stage 1, Stage 2 and joint analysis. The double GC-corrected p-value for the joint analysis are 6.5E-8, 5.7E-8 and 1.8E-6 for rs2075064, rs6931262 and rs1294410, respectively.

Figure 2. Regional association plots for LHX2 and RREB1 in GIANT consortium with participants of European ancestry.

The blue arrow points to the index SNPs identified from the samples of African ancestry and red arrow points to the best SNPs in GIANT consortium samples of European ancestry.

Figure 3. Regional association plots for all confirmed loci from the GIANT locus interrogation.

Each figure is centered by the index SNP (big red) with rs-number and p-value information (stage 1 only); another big rectangle is the best SNP in African Americans, with information including MAF = minor allele frequency; linkage disequilibrium information in HapMap YRI and CEU; P_D, P_F, and P_J are the single GC-corrected p-value obtained from discovery cohorts only, follow-up cohorts and joint discovery and follow-up data, respectively. Double GC-corrected p-value can be found in Table 4 .