title: Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue.
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.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Crystal N
authors.initials: CN
authors.lastname: Marconett
authors.affiliation: 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.
authors.forename: Jubao
authors.initials: J
authors.lastname: Duan
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hyland
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Information Management Services Inc., Rockville, Maryland 20852, USA.
authors.forename: William
authors.initials: W
authors.lastname: Wheeler
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, USC Keck School of Medicine, Los Angeles, California 90089, USA.
authors.forename: Beiyun
authors.initials: B
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Campan
authors.affiliation: 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.
authors.forename: Diane S
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Weiyin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Bioinformatics Division, Department of Preventive Medicine, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Triche
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Laufey
authors.initials: L
authors.lastname: Amundadottir
authors.affiliation: Pathology/Histotechnology Laboratory, Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Warner
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Hutchinson
authors.affiliation: 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.
authors.forename: Po-Han
authors.initials: PH
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Brian S I
authors.initials: BS
authors.lastname: Chung
authors.affiliation: Unit of Epidemiology, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, University of Milan, Milan 20122, Italy.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Pesatori
authors.affiliation: Unit of Epidemiology, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, University of Milan, Milan 20122, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Consonni
authors.affiliation: Unit of Epidemiology, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, University of Milan, Milan 20122, Italy.
authors.forename: Pier Alberto
authors.initials: PA
authors.lastname: Bertazzi
authors.affiliation: Molecular Genetics Program, Center for Health Sciences, SRI, Menlo Park, California 94025, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Bergen
authors.affiliation: 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.
authors.forename: Mathew
authors.initials: M
authors.lastname: Freedman
authors.affiliation: Bioinformatics Division, Department of Preventive Medicine, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Siegmund
authors.affiliation: 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.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Berman
authors.affiliation: 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.
authors.forename: Zea
authors.initials: Z
authors.lastname: Borok
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Caporaso
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: 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.
authors.forename: Ite A
authors.initials: IA
authors.lastname: Laird-Offringa
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892, USA.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
mesh_terms: D001940:Breast / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000208:ethnology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics