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 Consonni, Pier Alberto 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 and Maria Teresa Landi ()
Additional contact information
Jianxin Shi: National Cancer Institute, NIH, DHHS
Crystal N. Marconett: USC/Norris Comprehensive Cancer Center, Keck School of Medicine
Jubao Duan: Center for Psychiatric Genetics, North Shore University Health System Research Institute, University of Chicago Pritzker School of Medicine
Paula L. Hyland: National Cancer Institute, NIH, DHHS
Peng Li: National Cancer Institute, NIH, DHHS
Zhaoming Wang: National Cancer Institute, NIH, DHHS
William Wheeler: Information Management Services Inc.
Beiyun Zhou: Will Rogers Institute Pulmonary Research Center, Critical Care and Sleep Medicine, USC Keck School of Medicine
Mihaela Campan: USC/Norris Comprehensive Cancer Center, Keck School of Medicine
Diane S. Lee: USC/Norris Comprehensive Cancer Center, Keck School of Medicine
Jing Huang: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, DHHS
Weiyin Zhou: National Cancer Institute, NIH, DHHS
Tim Triche: University of Southern California
Laufey Amundadottir: National Cancer Institute, NIH, DHHS
Andrew Warner: Pathology/Histotechnology Laboratory, Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research
Amy Hutchinson: National Cancer Institute, NIH, DHHS
Po-Han Chen: USC/Norris Comprehensive Cancer Center, Keck School of Medicine
Brian S. I. Chung: USC/Norris Comprehensive Cancer Center, Keck School of Medicine
Angela C. Pesatori: Unit of Epidemiology, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, University of Milan
Dario Consonni: Unit of Epidemiology, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, University of Milan
Pier Alberto Bertazzi: Unit of Epidemiology, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, University of Milan
Andrew W. Bergen: Molecular Genetics Program, Center for Health Sciences, SRI
Mathew Freedman: Program in Medical and Population Genetics, The Broad Institute
Kimberly D. Siegmund: University of Southern California
Benjamin P. Berman: University of Southern California
Zea Borok: USC/Norris Comprehensive Cancer Center, Keck School of Medicine
Nilanjan Chatterjee: National Cancer Institute, NIH, DHHS
Margaret A. Tucker: National Cancer Institute, NIH, DHHS
Neil E. Caporaso: National Cancer Institute, NIH, DHHS
Stephen J. Chanock: National Cancer Institute, NIH, DHHS
Ite A. Laird-Offringa: USC/Norris Comprehensive Cancer Center, Keck School of Medicine
Maria Teresa Landi: National Cancer Institute, NIH, DHHS

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms4365

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