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Post-GWAS methodologies for localisation of functional non-coding variants: ANGPTL3

Oldoni, F; Palmen, J; Giambartolomei, C; Howard, P; Drenos, F; Plagnol, V; Humphries, SE; ... Smith, AJ; + view all (2016) Post-GWAS methodologies for localisation of functional non-coding variants: ANGPTL3. Atherosclerosis , 246 pp. 193-201. 10.1016/j.atherosclerosis.2015.12.009. Green open access

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Abstract

Genome-wide association studies have confirmed the involvement of non-coding angiopoietin-like 3 (ANGPTL3) gene variants with coronary artery disease, levels of low-density lipoprotein cholesterol (LDL-C), triglycerides and ANGPTL3 mRNA transcript. Extensive linkage disequilibrium at the locus, however, has hindered efforts to identify the potential functional variants. Using regulatory annotations from ENCODE, combined with functional in vivo assays such as allele-specific formaldehyde-assisted isolation of regulatory elements, statistical approaches including eQTL/lipid colocalisation, and traditional in vitro methodologies including electrophoretic mobility shift assay and luciferase reporter assays, variants affecting the ANGPTL3 regulome were examined. From 253 variants associated with ANGPTL3 mRNA expression, and/or lipid traits, 46 were located within liver regulatory elements and potentially functional. One variant, rs10889352, demonstrated allele-specific effects on DNA-protein interactions, reporter gene expression and chromatin accessibility, in line with effects on LDL-C levels and expression of ANGPTL3 mRNA. The ANGPTL3 gene lies within DOCK7, although the variant is within non-coding regions outside of ANGPTL3, within DOCK7, suggesting complex long-range regulatory effects on gene expression. This study illustrates the power of combining multiple genome-wide datasets with laboratory data to localise functional non-coding variation and provides a model for analysis of regulatory variants from GWAS.

Type: Article
Title: Post-GWAS methodologies for localisation of functional non-coding variants: ANGPTL3
Location: Ireland
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.atherosclerosis.2015.12.009
Publisher version: http://dx.doi.org/10.1016/j.atherosclerosis.2015.1...
Language: English
Additional information: Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Keywords: ANGPTL3, Chromatin, FAIRE, Functional polymorphism, Genome-wide, LDL-C, Polymorphism, Regulation
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Centre for Cardiovascular Genetics
URI: https://discovery.ucl.ac.uk/id/eprint/1477553
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