Cited by 155Epigenetics and DNA MethylationGenetic Associations and EpidemiologyGenomics and Chromatin Dynamics

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

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Shi, Jianxin, Marconett, Crystal N., Duan, Jubao, Hyland, Paula L., Li, Peng, Wang, Zhaoming, Wheeler, William, Zhou, Beiyun +24 more·2014·Nature Communications

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.

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  1. Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012). · DOI · Paper page

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Authors
Shi, J., Marconett, C. N., Duan, J., Hyland, P. L., Li, P., Wang, Z., Wheeler, W., Zhou, B., Campan, M., Lee, D. S., Huang, J., Zhou, W., Triche, T., Amundadottir, L., Warner, A., Hutchinson, A., Chen, P.-H., Chung, B. S. I., Pesatori, A. C., Consonni, D., Bertazzi, P. A., Bergen, A. W., Freedman, M., Siegmund, K. D., Berman, B. P., Borok, Z., Chatterjee, N., Tucker, M. A., Caporaso, N. E., Chanock, S. J., Laird-Offringa, I. A., & Landi, M. T.
Affiliations
  • United States Department of Health and Human Services (US)
  • University of Southern California (US)
  • Endeavor Health (US)
  • Information Management Services (US)
  • Frederick National Laboratory for Cancer Research (US)
  • University of Milan (IT)
  • SRI International (US)
  • Broad Institute (US)
Corresponding author
Landi, Maria Teresa
Venue
Nature Communications
Published
2014-02-27
Volume
5
Issue
1
Pages
3365-3365
ISSN
2041-1723 (ISSN-L)
OpenAlex
W2094251872
Cited by
137
References
66
Citations by year
2026: 1 · 2025: 3 · 2024: 9 · 2023: 5 · 2022: 6 · 2021: 11 · 2020: 10 · 2019: 14 · 2018: 17 · 2017: 15 · 2016: 21 · 2015: 20 · 2014: 5
FWCI
8.34
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Funders
  • National Institutes of Health (P30 H101258, HSN261200800001E)
  • U.S. Public Health Service (HSN261200800001E, 1 P30 H101258)
  • National Heart, Lung, and Blood Institute (R37HL062569, R01HL114094)
  • National Institute of Mental Health (R21MH102685)
  • National Cancer Institute (U19CA148127, HSN261200800001E, N02 CP001006, ZIACP010200, P30CA014089)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
DNA methylation, methylation quantitative trait loci, lung tissue, genetic-epigenetic interaction, CpG islands, CTCF binding sites, DNase I hypersensitivity, histone modifications, lung carcinogenesis, breast tissue, kidney tissue
MeSH terms
Breast, Epistasis, Genetic, Genotype, Humans, Kidney, Lung, Lung Neoplasms, Promoter Regions, Genetic, Risk Factors, Genetic Variation, CpG Islands, DNA Methylation, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, White People, Genome-Wide Association Study

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