期刊
NATURE COMMUNICATIONS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms4365
关键词
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资金
- Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics
- NCI [P30CA014089]
- Trandisciplinary Research in Cancer of the Lung (TRICL)
- Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19CA148127]
- NCI
- NIH [HSN261200800001E, 1 R01 HL114094, 1 P30 H101258, R37HL062569-13]
- Whittier Foundation
- Hastings Foundation
- Ralph Edgington Chair in Medicine
- ACS/Canary postdoctoral fellowship [PFTED-10-207-01-SIED]
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.
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