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Epigenetic modification such as DNA methylation plays a key role in disease susceptibility and gene regulation. However, the genetic regulation of DNA methylation in human is not fully appreciated. We describe the effects of genetic variants on the DNA methylome in human lung based on Based on the Environment And Genetics of Lung Etiology (EAGLE) study in the Division of Cancer Epidemiology and Genetics (DCEG) of NCI, we performed a methylation-quantitative trait loci (meQTL) analysesanalysis in 210 histologically normal human lung tissues. We identified 34,304 cis- and 585 trans-meQTLs, a genetic-epigenetic interaction of surprising magnitude. 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. We also develop developed a novel statistical algorithm and identified an association hotspot with replication in The Cancer Genome Atlas (TCGA) samples. |
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