Abstract MP60: Fine Mapping of Body Fat Distribution Loci in African American Populations: The Population Architecture Using Genomics and Epidemiology (PAGE) Study

Abstract

Introduction: Waist-to-hip ratio (WHR) is associated with cardiometabolic disease and its risk factors independent of body-mass-index (BMI). Previous GWAS on WHR adjusting for BMI (WHR’) have identified several SNPs but mainly among European descent populations (EA SNPs). While these SNPs point to general loci of interest, they are not likely the causal variants. Expanding analyses of these loci to other race and ethnic populations can dually assess whether these loci apply to more diverse populations and utilize differences in genetic linkage disequilibrium (LD) patterns to narrow the region containing the causal variant. Objective: To better capture genetic variants of WHR’ in self-identified African Americans (AA) within 14 loci containing previously reported WHR’ EA SNPs. Methods: Up to 14,322 AA participants (aged 20-93 years, 61% female) were included from seven studies. Individuals were genotyped using the Illumina iSelect Metabochip array consisting of nearly 200,000 SNPs enriched to fine map GWAS signals of cardiometabolic traits, including the 14 WHR’ loci. We modeled WHR’ adjusting for age, sex, study site, and the first three ancestry principle components for each study and conducted an inverse variance weighted meta-analysis. Variants reaching a Bonferroni adjusted threshold of P <0.0035 (0.05/14 loci) were considered significant (AA SNPs). Results: Within the 14 regions, seven loci (in or near TBX15-WARS2, DNM3-PIGC, GRB14, NISCH-STAB1, ADAMTS9, VEGFA, and RSPO3 ) contained a significant AA SNP. In the GRB14 locus, the AA SNP (rs10195252, P =1.93x10 -06 ) was the same as the EA SNP. Among four of the seven loci, the AA SNPs (rs12096179 near TBX15-WARS2, rs2371767 in ADAMTS9 , rs1358990 near VEGFA, and rs9385487 in RSPO3 ) were not independent of the EA SNPs (LD r 2 ≥0.3), but were more significant in AA, possibly narrowing the region containing the functional variant. Two AA SNPs (rs11715796 in NISCH-STAB1 and rs4916251 near DNM3-PIGC ) suggesting independence from the EA SNP (r 2 <0.3) were examined via conditional analyses. The AA SNP in NISCH-STAB1 had a stronger association after conditioning on the EA SNP, signifying independence. The AA SNP near DNM3-PIGC was less significant after conditioning, indicating it points to the same signal as the EA SNP. We have identified participants from additional cohorts for inclusion in future analyses and will conduct a sex-stratified analysis to further explore WHR’ loci among AA. Conclusions: Examination of 14 previously identified loci for WHR’ in AA individuals revealed one novel signal in NISCH-STAB1 . Five additional non-independent AA SNPs suggested a narrower region containing the WHR’ altering variant based on the LD structure differences between EA and AA. These findings highlight the value in expanding genetic association studies to other race and ethnic populations.