Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences

Loci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified in the Metabolic Syndrome in Men (METSIM) study. With GWAS data for 9,262 men, four loci were significantly associated with adiponectin:ADIPOQ,CDH13,IRS1, and PBRM1. We performed stepwise conditional analyses to identify distinct association signals, a subset of which are also nearly independent (lead variant pairwise r(2)<0.01). Two loci exhibited allelic heterogeneity,ADIPOQandCDH13. Of seven association signals at theADIPOQlocus, two signals colocalized with adipose tissue expression quantitative trait loci (eQTLs) for three transcripts: trait-increasing alleles at one signal were associated with increased ADIPOQ and LINC02043, while trait-increasing alleles at the other signal were associated with decreasedADIPOQ-AS1. In reporter assays, adiponectin-increasing alleles at two signals showed corresponding directions of effect on transcriptional activity. Putative mechanisms for the sevenADIPOQsignals include a missense variant (ADIPOQG90S), a splice variant, a promoter variant, and four enhancer variants. Of two association signals at theCDH13locus, the first signal consisted of promoter variants, including the lead adipose tissue eQTL variant forCDH13, while a second signal included a distal intron 1 enhancer variant that showed similar to 2-fold allelic differences in transcriptional reporter activity. Fine-mapping and experimental validation demonstrated that multiple, distinct association signals at these loci can influence multiple transcripts through multiple molecular mechanisms.