Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus

Authors

Maren E. Cannon, University of North Carolina at Chapel Hill
Qing Duan, University of North Carolina at Chapel Hill
Ying Wu, University of North Carolina at Chapel Hill
Monica Zeynalzadeh, University of North Carolina at Chapel Hill
Zheng Xu, University of North Carolina at Chapel Hill
Antti J. Kangas, University of Oulu
Pasi Soininen, University of Eastern Finland
Mika Ala-Korpela, University of Bristol
Mete Civelek, University of Virginia
Aldons J. Lusis, University of California, Los Angeles
Johanna Kuusisto, University of Eastern Finland
Francis S. Collins, National Institutes of Health, Maryland
Michael Boehnke, University of Michigan-Ann Arbor
Hua Tang, Stanford University
Markku Laakso, University of Eastern Finland
Yun Li, University of North Carolina at Chapel Hill
Karen L. Mohlke, University of North Carolina at Chapel HillFollow

ORCID IDs

0000-0001-6721-153X

Date of this Version

2017

Citation

Genes | Genomes | Genetics Volume 7, September 2017

Comments

Copyright © 2017 Cannon et al.

Open access

https://doi.org/10.1534/g3.117.300088

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.