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

Jianxin Shi, Crystal N. Marconett, Jubao Duan, Paula L. Hyland, Peng Li, Zhaoming Wang, William Wheeler, Beiyun Zhou, Mihaela Campan, Diane S. Lee, Jing Huang, Weiyin Zhou, Tim Triche, Laufey Amundadottir, Andrew Warner, Amy Hutchinson, Po Han Chen, Brian S.I. Chung, Angela C. Pesatori, Dario ConsonniPier A.lberto Bertazzi, Andrew W. Bergen, Mathew Freedman, Kimberly D. Siegmund, Benjamin P. Berman, Zea Borok, Nilanjan Chatterjee, Margaret A. Tucker, Neil E. Caporaso, Stephen J. Chanock, Ite A. Laird-Offringa, Maria T.eresa Landi

Research output: Contribution to journalArticlepeer-review

105 Scopus citations


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.

Original languageAmerican English
Article number3365
Pages (from-to)3365
Number of pages1
JournalNature Communications
StatePublished - 2014
Externally publishedYes

Bibliographical note

Funding Information:
This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD, USA ( We are grateful to the EAGLE participants and the large number of EAGLE collaborators (listed in, The Cancer Genome Atlas project for the genotype and methylation data and the ENCODE project for the regulatory region data. This work was supported by the Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics and, in part, by the Norris Comprehensive Cancer Center core grant (P30CA014089) from NCI, the Trandisciplinary Research in Cancer of the Lung (TRICL) and the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network (U19CA148127). A.W., Z.W., W.Z. and A.H. were also funded by the NCI, NIH (HSN261200800001E). I.A.L.-O. and Z.B. were also funded by NIH grants (1 R01 HL114094, 1 P30 H101258, and R37HL062569-13), Whittier Foundation and Hastings Foundation. Z.B. was also funded by the Ralph Edgington Chair in Medicine. C.N.M. was funded by ACS/Canary postdoctoral fellowship (PFTED-10-207-01-SIED).


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