University of Oulu

Cannon, M. E., Duan, Q., Wu, Y., Zeynalzadeh, M., Xu, Z., Kangas, A. J., … Mohlke, K. L. (2017). Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus. G3: Genes|Genomes|Genetics, 7(9), 3217–3227. https://doi.org/10.1534/g3.117.300088

Trans-ancestry fine mapping and molecular assays identify regulatory variants at the ANGPTL8 HDL-C GWAS locus

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Author: Cannon, Maren E.1; Duan, Qing1; Wu, Ying1;
Organizations: 1Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599
2Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, 90014 Finland
3NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, 70600 Finland
4School of Social and Community Medicine, University of Bristol
5Medical Research Council Integrative Epidemiology Unit at the University of Bristol, BS8 1TH United Kingdom
6Center for Public Health Genomics and Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22904
7Department of Medicine, Department of Human Genetics, Molecular Biology Institute, Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90095
8Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, 70600 Finland
9National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892
10Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109
11Department of Genetics, Stanford University, California 94305
12nstitute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, 70600 Finland
13Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27599
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2019081223874
Language: English
Published: Genetics Society of America, 2017
Publish Date: 2019-08-12
Description:

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.

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Series: G3. Genes, genomes, genetics
ISSN: 2160-1836
ISSN-E: 2160-1836
ISSN-L: 2160-1836
Volume: 7
Issue: 9
Pages: 3217 - 3227
DOI: 10.1534/g3.117.300088
OADOI: https://oadoi.org/10.1534/g3.117.300088
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Subjects:
Funding: This study was supported by NIH grants F31HL127984 (to M.E.C.), R01DK093757 (to K.L.M.), R01DK072193 (to K.L.M.), U01DK105561 (to K.L.M.), U01DK062370 (to M.B.), R00HL121172 (to M.C.), R01HG006292 (to Y.L.), R01HG006703 (to Y.L.), R01HL129132 (to Y.L.), and 1-ZIA-HG000024 (to F.S.C.); Academy of Finland grants 77299 and 124243 (to M.L.); the Finnish Heart Foundation (to M.L.); the Finnish Diabetes Foundation (to M.L.); Kuopio University Hospital State Research Funding (Valtion tutkimusrahoitus, VTR) grant (toM.L.); and the Commission of the European Community grant HEALTH-F2-582 2007-201681 (to M.L.). The serum nuclear magnetic resonance spectroscopy (NMR) metabolomics was supported by the Sigrid Juselius Foundation and the Strategic Research Funding from the University of Oulu. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. A.J.K. and P.S. are shareholders of Brainshake Ltd., a company offering NMR-based metabolite profiling. A.J.K. and P.S. report employment relations for Brainshake Ltd.
Copyright information: Copyright © 2017 Cannon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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