Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus
Year: 2017
Type: article
Abstract: Recent genome-wide association studies (GWAS) have identified variants associated with high-density lipoprotein cholesterol (HDL-C) located in or near the ANGPTL8 gene. Given the extensive sharing of GWAS loci across populations, we hypothesized that at least one shared variant at this locus affects HDL-C. The HDL-C–associated variants are coincident with expression quantitative trait loci for ANGPTL8 and DOCK6 in subcutaneous adipose tissue; however, only ANGPTL8 expression levels are associated with HDL-C levels. We identified a 400-bp promoter region of ANGPTL8 and enhancer regions within 5 kb that contribute to regulating expression in liver and adipose. To identify variants functionally responsible for the HDL-C association, we performed fine-mapping analyses and selected 13 candidate variants that overlap putative regulatory regions to test for allelic differences in regulatory function. Of these variants, rs12463177-G increased transcriptional activity (1.5-fold, P = 0.004) and showed differential protein binding. Six additional variants (rs17699089, rs200788077, rs56322906, rs3760782, rs737337, and rs3745683) showed evidence of allelic differences in transcriptional activity and/or protein binding. Taken together, these data suggest a regulatory mechanism at the ANGPTL8 HDL-C GWAS locus involving tissue-selective expression and at least one functional variant.
Source: G3 Genes Genomes Genetics
Institutions: University of North Carolina at Chapel Hill, University of Oulu, University of Eastern Finland, University of Bristol, MRC Integrative Epidemiology Unit, University of Virginia, University of California, Los Angeles, Kuopio University Hospital, National Institutes of Health, National Human Genome Research Institute, University of Michigan, Stanford University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,709
Awards: Systems genetics analysis of cardiometabolic trait loci in humans , Targeted Genetic Analysis of T2D and Quantitative Traits, G2478079187, Design and Analysis of Sequencing-based Studies for Complex Human Traits, G2988741787, G301048564, Genetic Studies of Blood Cell Traits in Multi-Ethnic Cohorts, Functional genetic variants for type 2 diabetes, Imputation and Analysis of Rare Variants in Admixed Populations, Genetic and metabolic effects on ANGPTL8 expression and HDL-C metabolism, G9000023558, G9000078064, G9000141698, G9000239990, G9000321097, Michigan Diabetes Research Center (MDRC)
OpenAlex ID: W2741959098