title: Epigenetics meets metabolomics: an epigenome-wide association study with blood serum metabolic traits.
abstract: Previously, we reported strong influences of genetic variants on metabolic phenotypes, some of them with clinical relevance. Here, we hypothesize that DNA methylation may have an important and potentially independent effect on human metabolism. To test this hypothesis, we conducted what is to the best of our knowledge the first epigenome-wide association study (EWAS) between DNA methylation and metabolic traits (metabotypes) in human blood. We assess 649 blood metabolic traits from 1814 participants of the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) population study for association with methylation of 457 004 CpG sites, determined on the Infinium HumanMethylation450 BeadChip platform. Using the EWAS approach, we identified two types of methylome-metabotype associations. One type is driven by an underlying genetic effect; the other type is independent of genetic variation and potentially driven by common environmental and life-style-dependent factors. We report eight CpG loci at genome-wide significance that have a genetic variant as confounder (P = 3.9 × 10(-20) to 2.0 × 10(-108), r(2) = 0.036 to 0.221). Seven loci display CpG site-specific associations to metabotypes, but do not exhibit any underlying genetic signals (P = 9.2 × 10(-14) to 2.7 × 10(-27), r(2) = 0.008 to 0.107). We further identify several groups of CpG loci that associate with a same metabotype, such as 4-vinylphenol sulfate and 4-androsten-3-beta,17-beta-diol disulfate. In these cases, the association between CpG-methylation and metabotype is likely the result of a common external environmental factor, including smoking. Our study shows that analysis of EWAS with large numbers of metabolic traits in large population cohorts are, in principle, feasible. Taken together, our data suggest that DNA methylation plays an important role in regulating human metabolism.
authors.affiliation: Institute of Genetic Epidemiology.
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Petersen
authors.forename: Sonja
authors.initials: S
authors.lastname: Zeilinger
authors.forename: Gabi
authors.initials: G
authors.lastname: Kastenmüller
authors.forename: Werner
authors.initials: W
authors.lastname: Römisch-Margl
authors.forename: Markus
authors.initials: M
authors.lastname: Brugger
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.forename: Christine
authors.initials: C
authors.lastname: Meisinger
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Philipp
authors.initials: P
authors.lastname: Pagel
authors.forename: Fritz
authors.initials: F
authors.lastname: Huber
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
mesh_terms: D000328:Adult; D000368:Aged; D001769:Blood / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D059647:Gene-Environment Interaction; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged; D040641:Quantitative Trait Loci; D012907:Smoking / Q000235:genetics