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Pleiotropic effects of trait-associated genetic variation on DNA methylation: utility for refining GWAS loci

Hannon, Eilis, Weedon, Mike, Bray, Nicholas ORCID:, O'Donovan, Michael ORCID: and Mill, Jonathan 2017. Pleiotropic effects of trait-associated genetic variation on DNA methylation: utility for refining GWAS loci. American Journal of Human Genetics 100 (6) , pp. 954-959. 10.1016/j.ajhg.2017.04.013

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Most genetic variants identified in genome-wide association studies (GWAS) of complex traits are thought to act via effects on gene regulation rather than directly altering the protein product. As a consequence, the actual genes involved in disease are not necessarily the most proximal to the associated variants. By integrating data from GWAS analyses with that from genetic studies of regulatory variation, it is possible to identify variants pleiotropically-associated with both a complex trait and measures of gene regulation. In this study, we use Summary data–based Mendelian Randomization (SMR), a method developed to identify variants pleiotropically associated with both complex traits and gene expression, to identify variants that are associated with complex traits and DNA methylation. We use large DNA methylation quantitative trait loci (mQTL) datasets generated from two different tissues (blood and fetal brain) to prioritize genes for >40 complex traits with robust GWAS data, highlighting considerable overlap with the results of SMR analyses performed using expression QTL (eQTL) data. We identify multiple examples of variable DNA methylation associated with GWAS variants for a range of complex traits, demonstrating the utility of this approach for refining genetic association signals.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
Additional Information: This is an open access article under the terms of the CC-BY Attribution 4.0 International license.
Publisher: Elsevier (Cell Press)
ISSN: 0002-9297
Date of First Compliant Deposit: 25 April 2017
Date of Acceptance: 19 April 2017
Last Modified: 20 Oct 2023 06:32

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