Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue
Open accessAbstract
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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In numerous examples, disease-associated loci were suggested to function through regulation of gene expression or modification of epigenetic markers.
“In numerous examples, the disease-associated loci were hinted to function via the regulation of gene expression or the modification of epigenetic markers (Liu, Aryee, et al.; Shi et al., 2014).”
From Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases (2016) · cites this paper as Shi et al., 2014
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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
- ORCID
- Shi, Jianxin
- Marconett, Crystal N.
- Duan, Jubao
- Hyland, Paula L.
- Li, Peng
- Wang, Zhaoming
- Wheeler, William
- Zhou, Beiyun
- Huang, Jing
- Zhou, Weiyin
- Amundadottir, Laufey
- Warner, Andrew
- Hutchinson, Amy
- Chen, Po-Han
- Pesatori, Angela C.
- Consonni, Dario
- Bertazzi, Pier Alberto
- Bergen, Andrew W.
- Siegmund, Kimberly D.
- Berman, Benjamin P.
- Borok, Zea
- Chatterjee, Nilanjan
- Tucker, Margaret A.
- Caporaso, Neil E.
- Chanock, Stephen J.
- Landi, Maria Teresa
- Venue
- Nature Communications
- Published
- 2014-02-27
- Volume
- 5
- Issue
- 1
- Pages
- 3365-3365
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3982882
- 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
- bronze
- doi.org
- Licence
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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