1. Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus.
- Author
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Cannon, Maren E., Qing Duan, Ying Wu, Zeynalzadeh, Monica, Zheng Xu, Kangas, Antti J., Soininen, Pasi, Ala-Korpela, Mika, Civelek, Mete, Lusis, Aldons J., Kuusisto, Johanna, Collins, Francis S., Boehnke, Michael, Hua Tang, Laakso, Markku, Yun Li, and Mohlke, Karen L.
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HIGH density lipoproteins , *CHOLESTEROL , *GENE expression - Abstract
Recent genome-wide association studies (GWAS) have identified variants associated with highdensity 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. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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