title: Systematic identification of genetic influences on methylation across the human life course.
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.
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK. tom.gaunt@bristol.ac.uk.
authors.forename: Tom R
authors.identifier: http://orcid.org/0000-0003-0924-3247
authors.initials: TR
authors.lastname: Gaunt
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors.forename: Hashem A
authors.initials: HA
authors.lastname: Shihab
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors.forename: Gibran
authors.initials: G
authors.lastname: Hemani
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors.forename: Josine L
authors.initials: JL
authors.lastname: Min
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors.forename: Geoff
authors.initials: G
authors.lastname: Woodward
authors.affiliation: Avon Longitudinal Study of Parents and Children (ALSPAC) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Lyttleton
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Avon Longitudinal Study of Parents and Children (ALSPAC) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors.forename: Aparna
authors.initials: A
authors.lastname: Duggirala
authors.affiliation: Avon Longitudinal Study of Parents and Children (ALSPAC) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: McArdle
authors.affiliation: Avon Longitudinal Study of Parents and Children (ALSPAC) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Ho
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.|Avon Longitudinal Study of Parents and Children (ALSPAC) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.|University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, 4102, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) & School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.|Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Relton
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D004247:DNA / Q000097:blood*; D019175:DNA Methylation; D030541:Databases, Genetic; D044127:Epigenesis, Genetic; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D007231:Infant, Newborn; D008875:Middle Aged; D011247:Pregnancy; D040641:Quantitative Trait Loci
chemical_list: D004247:DNA
keywords: Cohort; DNA methylation; Genetic association; Methylation quantitative trait loci; mQTL