Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue

Nat Commun. 2014 Feb 27;5:3365. doi: 10.1038/ncomms4365.

Abstract

The genetic regulation of the human epigenome is not fully appreciated. Here we describe the effects of genetic variants on the DNA methylome in human lung based on methylation-quantitative trait loci (meQTL) analyses. We report 34,304 cis- and 585 trans-meQTLs, a genetic-epigenetic interaction of surprising magnitude, including a regulatory hotspot. These findings are replicated in both breast and kidney tissues and show distinct patterns: cis-meQTLs mostly localize to CpG sites outside of genes, promoters and CpG islands (CGIs), while trans-meQTLs are over-represented in promoter CGIs. meQTL SNPs are enriched in CTCF-binding sites, DNaseI hypersensitivity regions and histone marks. Importantly, four of the five established lung cancer risk loci in European ancestry are cis-meQTLs and, in aggregate, cis-meQTLs are enriched for lung cancer risk in a genome-wide analysis of 11,587 subjects. Thus, inherited genetic variation may affect lung carcinogenesis by regulating the human methylome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast / metabolism
  • CpG Islands / genetics
  • DNA Methylation*
  • Epistasis, Genetic
  • European Continental Ancestry Group / genetics
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics
  • Genetic Variation*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Kidney / metabolism
  • Lung / metabolism*
  • Lung Neoplasms / ethnology
  • Lung Neoplasms / genetics
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic / genetics
  • Quantitative Trait Loci / genetics*
  • Risk Factors

Associated data

  • dbGaP/GSE52401
  • dbGaP/PHS000093