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Nat Commun DOI:10.1038/ncomms4365

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

Publication TypeJournal Article
Year of Publication2014
AuthorsShi, J, Marconett, CN, Duan, J, Hyland, PL, Li, P, Wang, Z, Wheeler, W, Zhou, B, Campan, M, Lee, DS, Huang, J, Zhou, W, Triche, T, Amundadottir, L, Warner, A, Hutchinson, A, Chen, P-H, Chung, BSI, Pesatori, AC, Consonni, D, Bertazzi, PAlberto, Bergen, AW, Freedman, M, Siegmund, KD, Berman, BP, Borok, Z, Chatterjee, N, Tucker, MA, Caporaso, NE, Chanock, SJ, Laird-Offringa, IA, Landi, MTeresa
JournalNat Commun
Date Published2014 Feb 27
KeywordsBreast, CpG Islands, DNA Methylation, Epistasis, Genetic, European Continental Ancestry Group, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Kidney, Lung, Lung Neoplasms, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Quantitative Trait Loci, Risk Factors

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.


Alternate JournalNat Commun
PubMed ID24572595
PubMed Central IDPMC3982882
Grant ListU19 CA148127 / CA / NCI NIH HHS / United States
1 P30 H101258 / / PHS HHS / United States
R37HL062569-13 / HL / NHLBI NIH HHS / United States
R21 MH102685 / MH / NIMH NIH HHS / United States
P30CA014089 / CA / NCI NIH HHS / United States
ZIA CP010200-03 / / Intramural NIH HHS / United States
R01 HL114094 / HL / NHLBI NIH HHS / United States
N02-CP-01006 / CP / NCI NIH HHS / United States
1 R01 HL114094 / HL / NHLBI NIH HHS / United States
P30 CA014089 / CA / NCI NIH HHS / United States
HSN261200800001E / / PHS HHS / United States
U19CA148127 / CA / NCI NIH HHS / United States
R37 HL062569 / HL / NHLBI NIH HHS / United States