Systematic identification of genetic influences on methylation across the human life course

Tom Gaunt, Hashem Shihab, Gibran Hemani, Josine Min, Geoff Woodward, Oliver Lyttleton, Jie Zheng, Aparna Duggirala, Wendy McArdle, Karen Ho, Susan Ring, David Evans, George Davey Smith, Caroline Relton

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Abstract

Background
The influence of genetic variation on complex diseases is potentially mediated through a range of highly dynamic epigenetic processes exhibiting temporal variation during development and later life. Here we present a catalogue of the genetic influences on DNA methylation (methylation quantitative trait loci (mQTL)) at five different life stages in human blood: children at birth, childhood, adolescence and their mothers during pregnancy and middle age.

Results
We show that genetic effects on methylation are highly stable across the life course and that developmental change in the genetic contribution to variation in methylation occurs primarily through increases in environmental or stochastic effects. Though we map a large proportion of the cis-acting genetic variation, a much larger component of genetic effects influencing methylation are acting in trans. However, only 7 % of discovered mQTL are trans-effects, suggesting that the trans component is highly polygenic. Finally, we estimate the contribution of mQTL to variation in complex traits and infer that methylation may have a causal role consistent with an infinitesimal model in which many methylation sites each have a small influence, amounting to a large overall contribution.

Conclusions
DNA methylation contains a significant heritable component that remains consistent across the lifespan. Our results suggest that the genetic component of methylation may have a causal role in complex traits. The database of mQTL presented here provide a rich resource for those interested in investigating the role of methylation in disease.
Original languageEnglish
Article number61
Number of pages14
JournalGenome Biology
Volume17
DOIs
Publication statusPublished - 31 Mar 2016

Keywords

  • Methylation quantitative trait loci
  • mQTL
  • Cohort
  • Genetic association
  • DNA methylation

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  • Projects

    IEU Theme 2

    Flach, P. A., Gaunt, T. R. & Gaunt, T. R.

    1/06/1331/03/18

    Project: Research

    MRC UoB UNITE Unit - Programme 1

    Davey Smith, G.

    1/06/1331/03/18

    Project: Research

    MRC UoB UNITE Unit - Programme 2

    Relton, C. L. & Relton, C. L.

    1/06/1331/03/18

    Project: Research

    Datasets

    ARIES mQTL results

    Shihab, H. A. (Creator), Gaunt, T. R. (Creator), Relton, C. L. (Creator), Hemani, G. (Creator), Davey Smith, G. (Creator), Woodward, G. (Contributor), McArdle, W. L. (Contributor), Evans, D. M. (Contributor), Zheng, J. (Contributor), Min, J. L. (Contributor), Ho, K. M. (Contributor), Ring, S. M. (Contributor), Lyttleton, O. (Contributor), Duggirala, A. (Contributor) & Gaunt, T. R. (Data Manager), University of Bristol, 9 Mar 2016

    Dataset

    Equipment

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