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

Maren E Cannon, Qing Duan, Ying Wu, Monica Zeynalzadeh, Zheng Xu, Antti J Kangas, Pasi Soininen, Mika Ala-Korpela, Mete Civelek, Aldons J Lusis, Johanna Kuusisto, Francis S Collins, Michael Boehnke, Hua Tang, Markku Laakso, Yun Li, Karen L Mohlke

Research output: Contribution to journalArticle (Academic Journal)peer-review

16 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)3217-3227
Number of pages11
Issue number9
Early online date7 Sept 2017
Publication statusPublished - Sept 2017


  • Aged
  • Alleles
  • Angiopoietin-like Proteins/genetics
  • Animals
  • Cell Line
  • Cholesterol, HDL/genetics
  • Chromosome Mapping
  • Enhancer Elements, Genetic
  • Gene Expression
  • Genes, Reporter
  • Genetic Association Studies
  • Genetic Variation
  • Genome-Wide Association Study
  • Haplotypes
  • Humans
  • Male
  • Metabolic Syndrome/epidemiology
  • Mice
  • Middle Aged
  • Organ Specificity/genetics
  • Peptide Hormones/genetics
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Quantitative Trait Loci
  • Quantitative Trait, Heritable
  • Regulatory Sequences, Nucleic Acid
  • Subcutaneous Fat/metabolism


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