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

Author

Listed:
  • Jianxin Shi

    (National Cancer Institute, NIH, DHHS)

  • Crystal N. Marconett

    (USC/Norris Comprehensive Cancer Center, Keck School of Medicine
    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
    USC/Norris Comprehensive Cancer Center, Keck School of Medicine)

  • Diane S. Lee

    (USC/Norris Comprehensive Cancer Center, Keck School of Medicine
    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
    USC/Norris Comprehensive Cancer Center, Keck School of Medicine)

  • Brian S. I. Chung

    (USC/Norris Comprehensive Cancer Center, Keck School of Medicine
    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
    The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute)

  • Kimberly D. Siegmund

    (University of Southern California)

  • Benjamin P. Berman

    (University of Southern California
    USC Epigenome Center and USC/Norris Comprehensive Cancer Center)

  • Zea Borok

    (USC/Norris Comprehensive Cancer Center, Keck School of Medicine
    Will Rogers Institute Pulmonary Research Center, Critical Care and Sleep Medicine, USC 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
    USC/Norris Comprehensive Cancer Center, Keck School of Medicine)

  • Maria Teresa Landi

    (National Cancer Institute, NIH, DHHS)

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.

Suggested Citation

  • 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 & La, 2014. "Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue," Nature Communications, Nature, vol. 5(1), pages 1-11, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4365
    DOI: 10.1038/ncomms4365
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    Cited by:

    1. Lulu Shang & Wei Zhao & Yi Zhe Wang & Zheng Li & Jerome J. Choi & Minjung Kho & Thomas H. Mosley & Sharon L. R. Kardia & Jennifer A. Smith & Xiang Zhou, 2023. "meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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