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

Document Type

Article

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.