title: Contribution of genetic variation to transgenerational inheritance of DNA methylation.
abstract: BACKGROUND
  Despite the important role DNA methylation plays in transcriptional regulation, the transgenerational inheritance of DNA methylation is not well understood. The genetic heritability of DNA methylation has been estimated using twin pairs, although concern has been expressed whether the underlying assumption of equal common environmental effects are applicable due to intrauterine differences between monozygotic and dizygotic twins. We estimate the heritability of DNA methylation on peripheral blood leukocytes using Illumina HumanMethylation450 array using a family based sample of 614 people from 117 families, allowing comparison both within and across generations.
  
  
  RESULTS
  The correlations from the various available relative pairs indicate that on average the similarity in DNA methylation between relatives is predominantly due to genetic effects with any common environmental or zygotic effects being limited. The average heritability of DNA methylation measured at probes with no known SNPs is estimated as 0.187. The ten most heritable methylation probes were investigated with a genome-wide association study, all showing highly statistically significant cis mQTLs. Further investigation of one of these cis mQTL, found in the MHC region of chromosome 6, showed the most significantly associated SNP was also associated with over 200 other DNA methylation probes in this region and the gene expression level of 9 genes.
  
  
  CONCLUSIONS
  The majority of transgenerational similarity in DNA methylation is attributable to genetic effects, and approximately 20% of individual differences in DNA methylation in the population are caused by DNA sequence variation that is not located within CpG sites.
authors.forename: Allan F
authors.initials: AF
authors.lastname: McRae
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Powell
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.forename: Lisa
authors.initials: L
authors.lastname: Bowdler
authors.forename: Gibran
authors.initials: G
authors.lastname: Hemani
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.forename: Jodie N
authors.initials: JN
authors.lastname: Painter
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
mesh_terms: D000328:Adult; D002877:Chromosomes, Human; D019175:DNA Methylation; D014644:Genetic Variation; D006801:Humans; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D014429:Twins, Dizygotic / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics*; D044465:White People / Q000235:genetics