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Mendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk

The extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies... Full description

Journal Title: American journal of human genetics 2017-10-05, Vol.101 (4), p.590-602
Main Author: Richardson, Tom G
Other Authors: Zheng, Jie , Davey Smith, George , Timpson, Nicholas J , Gaunt, Tom R , Relton, Caroline L , Hemani, Gibran
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0002-9297
Link: https://www.ncbi.nlm.nih.gov/pubmed/28985495
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title: Mendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk
format: Article
creator:
  • Richardson, Tom G
  • Zheng, Jie
  • Davey Smith, George
  • Timpson, Nicholas J
  • Gaunt, Tom R
  • Relton, Caroline L
  • Hemani, Gibran
subjects:
  • Adenylyl Cyclases - genetics
  • Adiponectin - genetics
  • Article
  • atira
  • cardiovascular disease
  • Cardiovascular diseases
  • Cardiovascular Diseases - epidemiology
  • Cardiovascular Diseases - genetics
  • Cardiovascular Diseases - pathology
  • causal inference
  • Child
  • Cohort Studies
  • CpG Islands
  • DNA Methlyation
  • DNA Methylation
  • Epigenetic
  • epigenome-wide association studies
  • Female
  • Gene expression
  • Gene Expression Regulation
  • Genetic aspects
  • Genetic variation
  • Genome, Human
  • Genome-wide association studies
  • Genome-Wide Association Study - methods
  • Humans
  • Journal Article
  • Mediation
  • Mendelian randomization
  • Mendelian Randomization Analysis - methods
  • Methylation
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Pregnancy
  • pubmedpublicationtype
  • pure
  • Quantitative Trait Loci
  • Research
  • researchoutput
  • Risk Factors
  • United Kingdom - epidemiology
  • Usage
ispartof: American journal of human genetics, 2017-10-05, Vol.101 (4), p.590-602
description: The extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits. We identified ten genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits after multiple-testing correction. Bivariate fine mapping provided evidence that the individual variants responsible for the observed effects on cardiovascular traits at the ADCY3 and ADIPOQ loci were potentially mediated through changes in DNA methylation, although we highlight that we are unable to reliably separate causality from horizontal pleiotropy. Estimates of causal effects were replicated with results from large-scale consortia. Genetic variants and CpG sites identified in this study were enriched for histone mark peaks in relevant tissue types and gene promoter regions. Integrating our results with expression quantitative trait loci data, we provide evidence that variation at these regulatory regions is likely to also influence gene expression levels at these loci.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
url: Link


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creatorRichardson, Tom G ; Zheng, Jie ; Davey Smith, George ; Timpson, Nicholas J ; Gaunt, Tom R ; Relton, Caroline L ; Hemani, Gibran
creatorcontribRichardson, Tom G ; Zheng, Jie ; Davey Smith, George ; Timpson, Nicholas J ; Gaunt, Tom R ; Relton, Caroline L ; Hemani, Gibran
descriptionThe extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits. We identified ten genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits after multiple-testing correction. Bivariate fine mapping provided evidence that the individual variants responsible for the observed effects on cardiovascular traits at the ADCY3 and ADIPOQ loci were potentially mediated through changes in DNA methylation, although we highlight that we are unable to reliably separate causality from horizontal pleiotropy. Estimates of causal effects were replicated with results from large-scale consortia. Genetic variants and CpG sites identified in this study were enriched for histone mark peaks in relevant tissue types and gene promoter regions. Integrating our results with expression quantitative trait loci data, we provide evidence that variation at these regulatory regions is likely to also influence gene expression levels at these loci.
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subjectAdenylyl Cyclases - genetics ; Adiponectin - genetics ; Article ; atira ; cardiovascular disease ; Cardiovascular diseases ; Cardiovascular Diseases - epidemiology ; Cardiovascular Diseases - genetics ; Cardiovascular Diseases - pathology ; causal inference ; Child ; Cohort Studies ; CpG Islands ; DNA Methlyation ; DNA Methylation ; Epigenetic ; epigenome-wide association studies ; Female ; Gene expression ; Gene Expression Regulation ; Genetic aspects ; Genetic variation ; Genome, Human ; Genome-wide association studies ; Genome-Wide Association Study - methods ; Humans ; Journal Article ; Mediation ; Mendelian randomization ; Mendelian Randomization Analysis - methods ; Methylation ; Phenotype ; Polymorphism, Single Nucleotide ; Pregnancy ; pubmedpublicationtype ; pure ; Quantitative Trait Loci ; Research ; researchoutput ; Risk Factors ; United Kingdom - epidemiology ; Usage
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titleMendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk
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abstractThe extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits. We identified ten genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits after multiple-testing correction. Bivariate fine mapping provided evidence that the individual variants responsible for the observed effects on cardiovascular traits at the ADCY3 and ADIPOQ loci were potentially mediated through changes in DNA methylation, although we highlight that we are unable to reliably separate causality from horizontal pleiotropy. Estimates of causal effects were replicated with results from large-scale consortia. Genetic variants and CpG sites identified in this study were enriched for histone mark peaks in relevant tissue types and gene promoter regions. Integrating our results with expression quantitative trait loci data, we provide evidence that variation at these regulatory regions is likely to also influence gene expression levels at these loci.
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