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Imputation of DNA Methylation Levels in the Brain Implicates a Risk Factor for Parkinson's Disease

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    Rights statement: Copyright © 2016 Rawlik et al. Available freely online through the author-supported open access option. 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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Original languageEnglish
Pages (from-to)771-781
JournalGenetics
Volume204
Issue number2
Early online date26 Jul 2016
DOIs
Publication statusPublished - Oct 2016

Abstract

Understanding how genetic variation affects intermediate phenotypes, like DNA methylation or gene expression, and how these in turn vary with complex human disease provides valuable insight into disease aetiology. However intermediate phenotypes are typically tissue and developmental stage specific, making relevant phenotype difficult to assay. Assembling large case-control cohorts, necessary to achieve sufficient statistical power to assess associations between complex traits and relevant intermediate phenotypes, has therefore remained challenging. Imputation of such intermediate phenotypes represents a practical alternative in this context. We used a mixed linear model to impute DNAm levels of four brain tissues at up to 1826 methylome wide sites in 6259 Parkinson's disease patients and 9452 controls from across five GWAS studies. Six sites, in two regions, were found to associate with Parkinson's disease for at least one tissue. While a majority of identified sites were within an established risk region for Parkinson's disease, suggesting a role of DNAm in mediating previously observed genetic effects at this locus, we also identify an association with four CpG sites in chromosome 16p11.2. Direct measures of DNAm in the Substantia Nigra of 39 cases and 13 control samples were used to independently replicate these four associations. Only the association at cg10917602 replicated with a concordant direction of effect (P=0.02). cg10917602 is and 87kb away from the closest reported GWAS hit. The employed imputation methodology implies that variation of DNAm levels at cg10917602 is predictive for Parkinson's disease risk, suggesting a possible causal role for methylation at this locus. More generally this study demonstrates the feasibility of identifying predictive epi-genetic markers of disease risk from readily available datasets.

    Research areas

  • DNA methylation, imputation, Parkinson’s disease

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