Epigenomic and transcriptomic prioritization of candidate obesity-risk regulatory GWAS SNPs

Concern about rising rates of obesity has prompted searches for its genetic risk determinants in genome-wide association studies (GWAS). Most genetic variants that contribute to the increased risk of a given trait are probably regulatory single nucleotide polymorphisms (SNPs). However, identifying plausible regulatory SNPs is difficult because of their varied locations relative to their target gene and linkage disequilibrium, which makes most GWAS-derived SNPs only proxies for many fewer functional SNPs. We developed a systematic approach to prioritizing GWAS-derived obesity SNPs using detailed epigenomic and transcriptomic analysis in adipose tissue vs. heterologous tissues. From 50 obesity-related GWAS and 121,064 expanded SNPs, we prioritized 47 potential causal regulatory SNPs (Tier-1 SNPs) for 14 gene loci. A detailed examination of seven of these genes revealed that four (CABLES1, PC, PEMT, and FAM13A) had Tier-1 SNPs that might regulate alternative use of transcription start sites resulting in different polypeptides being generated or different amounts of an intronic microRNA gene being expressed. HOXA11 and long noncoding RNA gene RP11-392O17.1 had Tier-1 SNPs in their 3-prime or promoter region, respectively, and strong preferences for expression in subcutaneous vs. visceral adipose tissue. ZBED3-AS1 had two intragenic Tier-1 SNPs, each of which might contribute to mediating obesity risk through modulating long-distance chromatin interactions. We conclude that prioritization of regulatory SNP candidates should focus on their surrounding epigenetic features in a trait-relevant tissue. Our approach not only revealed especially credible novel regulatory SNPs, but also helped evaluate previously highlighted obesity GWAS SNPs that were candidates for transcription regulation.