|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Shi, 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, PH, Chung, BS, Pesatori, AC, Consonni, D, Bertazzi, PA, Bergen, AW, Freedman, M, Siegmund, KD, Berman, BP, Borok, Z, Chatterjee, N, Tucker, MA, Caporaso, NE, Chanock, SJ, Laird-Offringa, IA, Landi, MT|
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.