Projects per year
Abstract
We have undertaken a systematic Mendelian randomization (MR) study using methylation quantitative trait loci (meQTL) as genetic instruments to assess the relationship between genetic variation, DNA methylation and 139 complex traits. Using two-sample MR, we identified 1148 associations across 61 traits where genetic variants were associated with both proximal DNA methylation (i.e. cis-meQTL) and complex trait variation (P<1.39 × 10-08). Joint likelihood mapping provided evidence that the genetic variant which influenced DNA methylation levels for 348 of these associations across 47 traits was also responsible for variation in complex traits. These associations showed a high rate of replication in the BIOS QTL and UK Biobank datasets for 14 selected traits, as 101 of the attempted 128 associations survived multiple testing corrections (P<3.91 × 10-04). Integrating expression quantitative trait loci (eQTL) data suggested that genetic variants responsible for 306 of the 348 refined meQTL associations also influence gene expression, which indicates a coordinated system of effects that are consistent with causality. CpG sites were enriched for histone mark peaks in tissue types relevant to their associated trait and implicated genes were enriched across relevant biological pathways. Though we are unable to distinguish mediation from horizontal pleiotropy in these analyses, our findings should prove valuable in prioritizing candidate loci where DNA methylation may influence traits and help develop mechanistic insight into the aetiology of complex disease.
Original language | English |
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Pages (from-to) | 3293-3304 |
Number of pages | 12 |
Journal | Human Molecular Genetics |
Volume | 27 |
Issue number | 18 |
Early online date | 8 Jun 2018 |
DOIs | |
Publication status | Published - Sept 2018 |
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Dive into the research topics of 'Systematic Mendelian randomization framework elucidates hundreds of CpG sites which may mediate the influence of genetic variants on disease'. Together they form a unique fingerprint.Projects
- 5 Finished
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(IEU) Epigenetics: Environment, Embodiment & Equality (E4)
Relton, C. L. (Principal Investigator)
1/01/16 → 31/12/19
Project: Research
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MRC UoB UNITE Unit - Programme 1
Davey Smith, G. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
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MRC UoB UNITE Unit - programme 3
Timpson, N. J. (Principal Investigator) & Timpson, N. J. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
Profiles
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Dr Tom G Richardson
- Bristol Medical School (PHS) - Honorary Senior Research Fellow
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit
Person: Member, Honorary and Visiting Academic