부산대학교 도서관

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 r2<0.01). Two loci exhibited allelic heterogeneity, ADIPOQ and CDH13. Of seven association signals at the ADIPOQ locus, 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 decreased ADIPOQ-AS1. In reporter assays, adiponectin-increasing alleles at two signals showed corresponding directions of effect on transcriptional activity. Putative mechanisms for the seven ADIPOQ signals include a missense variant (ADIPOQ G90S), a splice variant, a promoter variant, and four enhancer variants. Of two association signals at the CDH13 locus, the first signal consisted of promoter variants, including the lead adipose tissue eQTL variant for CDH13, while a second signal included a distal intron 1 enhancer variant that showed ~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. Author summary: Many DNA variants affect common human traits, and distinct variants can have different effects on the function or expression level of the same gene. We identified variants associated with levels of adiponectin, a hormone involved in glucose regulation. Among these variants, we specifically studied the sets of variants located near two genes, ADIPOQ and CDH13, to determine how the variants affect gene expression or function. We focused on sets of variants that can be inherited together but are not always inherited together. Of the variants associated with adiponectin and located near ADIPOQ, one set were also associated with higher expression levels of the protein-coding ADIPOQ gene and a nearby non-coding gene, a second set of variants were associated with lower levels of the ADIPOQ-AS1 antisense gene, and additional variants changed the amino acid sequence or size of the adiponectin protein. Our examples show the benefits of identifying multiple sets of trait-associated variants in the same DNA region. These variants explain more trait variation, help identify genes that affect the trait, and guide studies of gene regulation and biological processes. [ABSTRACT FROM AUTHOR]