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; Maria Teresa Landi

doi:10.1038/ncomms4365

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

Nat Commun. 2014 Feb 27:5:3365. doi: 10.1038/ncomms4365.

Authors

Jianxin Shi¹, Crystal N Marconett², Jubao Duan³, Paula L Hyland¹, Peng Li¹, Zhaoming Wang¹, William Wheeler⁴, Beiyun Zhou⁵, Mihaela Campan², Diane S Lee², Jing Huang⁶, Weiyin Zhou¹, Tim Triche⁷, Laufey Amundadottir¹, Andrew Warner⁸, Amy Hutchinson¹, Po-Han Chen², Brian S I Chung², Angela C Pesatori⁹, Dario Consonni⁹, Pier Alberto Bertazzi⁹, Andrew W Bergen¹⁰, Mathew Freedman¹¹, Kimberly D Siegmund⁷, Benjamin P Berman¹², Zea Borok¹³, Nilanjan Chatterjee¹, Margaret A Tucker¹, Neil E Caporaso¹, Stephen J Chanock¹, Ite A Laird-Offringa², Maria Teresa Landi¹

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
² 1] Department of Surgery, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, California 90089, USA [2] Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, California 90089, USA.
³ Center for Psychiatric Genetics, Department of Psychiatry and Behavioral Sciences, North Shore University Health System Research Institute, University of Chicago Pritzker School of Medicine, Evanston, Illinois 60201, USA.
⁴ Information Management Services Inc., Rockville, Maryland 20852, USA.
⁵ Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, USC Keck School of Medicine, Los Angeles, California 90089, USA.
⁶ Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
⁷ Bioinformatics Division, Department of Preventive Medicine, University of Southern California, Los Angeles, California 90089, USA.
⁸ Pathology/Histotechnology Laboratory, Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
⁹ Unit of Epidemiology, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, University of Milan, Milan 20122, Italy.
¹⁰ Molecular Genetics Program, Center for Health Sciences, SRI, Menlo Park, California 94025, USA.
¹¹ 1] Program in Medical and Population Genetics, The Broad Institute, Cambridge, Massachusetts 02142, USA [2] Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
¹² 1] Bioinformatics Division, Department of Preventive Medicine, University of Southern California, Los Angeles, California 90089, USA [2] USC Epigenome Center and USC/Norris Comprehensive Cancer Center, Los Angeles, California 90089, USA.
¹³ 1] Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, California 90089, USA [2] Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, USC Keck School of Medicine, Los Angeles, California 90089, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Breast / metabolism
CpG Islands / genetics
DNA Methylation*
Epistasis, Genetic
Genetic Predisposition to Disease / ethnology
Genetic Predisposition to Disease / genetics
Genetic Variation*
Genome-Wide Association Study
Genotype
Humans
Kidney / metabolism
Lung / metabolism*
Lung Neoplasms / ethnology
Lung Neoplasms / genetics
Polymorphism, Single Nucleotide
Promoter Regions, Genetic / genetics
Quantitative Trait Loci / genetics*
Risk Factors
White People / genetics

Associated data

dbGaP/GSE52401
dbGaP/PHS000093

Abstract

Publication types

MeSH terms

Associated data

Grants and funding