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 A.lberto 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 T.eresa Landi

doi:10.1038/ncomms4365

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 ConsonniPier A.lberto 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 T.eresa Landi

School of Medicine

Research output: Contribution to journal › Article › peer-review

88 Scopus citations

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.

Original language	English (US)
Article number	3365
Pages (from-to)	3365
Number of pages	1
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4365
State	Published - 2014

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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., ... Landi, M. T. E. (2014). Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue. Nature communications, 5, 3365. Article 3365. https://doi.org/10.1038/ncomms4365

Shi, J, Marconett, CN, Duan, J, Hyland, PL, Li, P, Wang, Z, Wheeler, W, Zhou, B, Campan, M, Lee, DS, Huang, J, Zhou, W, Triche, T, Amundadottir, L, Warner, A, Hutchinson, A, Chen, PH, Chung, BSI, Pesatori, AC, Consonni, D, Bertazzi, PAL, Bergen, AW, Freedman, M, Siegmund, KD, Berman, BP, Borok, Z, Chatterjee, N, Tucker, MA, Caporaso, NE, Chanock, SJ, Laird-Offringa, IA & Landi, MTE 2014, 'Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue', Nature communications, vol. 5, 3365, pp. 3365. https://doi.org/10.1038/ncomms4365

@article{a0b0c17ec05d493c9132319d4d2afa6b,

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. ",

author = "Jianxin Shi and Marconett, {Crystal N.} and Jubao Duan and Hyland, {Paula L.} and Peng Li and Zhaoming Wang and William Wheeler and Beiyun Zhou and Mihaela Campan and Lee, {Diane S.} and Jing Huang and Weiyin Zhou and Tim Triche and Laufey Amundadottir and Andrew Warner and Amy Hutchinson and Chen, {Po Han} and Chung, {Brian S.I.} and Pesatori, {Angela C.} and Dario Consonni and Bertazzi, {Pier A.lberto} and Bergen, {Andrew W.} and Mathew Freedman and Siegmund, {Kimberly D.} and Berman, {Benjamin P.} and Zea Borok and Nilanjan Chatterjee and Tucker, {Margaret A.} and Caporaso, {Neil E.} and Chanock, {Stephen J.} and Laird-Offringa, {Ite A.} and Landi, {Maria T.eresa}",

note = "Funding Information: This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD, USA (http://biowulf.nih.gov). We are grateful to the EAGLE participants and the large number of EAGLE collaborators (listed in http://dceg.cancer.gov/eagle), The Cancer Genome Atlas project for the genotype and methylation data and the ENCODE project for the regulatory region data. This work was supported by the Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics and, in part, by the Norris Comprehensive Cancer Center core grant (P30CA014089) from NCI, the Trandisciplinary Research in Cancer of the Lung (TRICL) and the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network (U19CA148127). A.W., Z.W., W.Z. and A.H. were also funded by the NCI, NIH (HSN261200800001E). I.A.L.-O. and Z.B. were also funded by NIH grants (1 R01 HL114094, 1 P30 H101258, and R37HL062569-13), Whittier Foundation and Hastings Foundation. Z.B. was also funded by the Ralph Edgington Chair in Medicine. C.N.M. was funded by ACS/Canary postdoctoral fellowship (PFTED-10-207-01-SIED).",

year = "2014",

doi = "10.1038/ncomms4365",

language = "English (US)",

volume = "5",

pages = "3365",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue

AU - Shi, Jianxin

AU - Marconett, Crystal N.

AU - Duan, Jubao

AU - Hyland, Paula L.

AU - Li, Peng

AU - Wang, Zhaoming

AU - Wheeler, William

AU - Zhou, Beiyun

AU - Campan, Mihaela

AU - Lee, Diane S.

AU - Huang, Jing

AU - Zhou, Weiyin

AU - Triche, Tim

AU - Amundadottir, Laufey

AU - Warner, Andrew

AU - Hutchinson, Amy

AU - Chen, Po Han

AU - Chung, Brian S.I.

AU - Pesatori, Angela C.

AU - Consonni, Dario

AU - Bertazzi, Pier A.lberto

AU - Bergen, Andrew W.

AU - Freedman, Mathew

AU - Siegmund, Kimberly D.

AU - Berman, Benjamin P.

AU - Borok, Zea

AU - Chatterjee, Nilanjan

AU - Tucker, Margaret A.

AU - Caporaso, Neil E.

AU - Chanock, Stephen J.

AU - Laird-Offringa, Ite A.

AU - Landi, Maria T.eresa

N1 - Funding Information: This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD, USA (http://biowulf.nih.gov). We are grateful to the EAGLE participants and the large number of EAGLE collaborators (listed in http://dceg.cancer.gov/eagle), The Cancer Genome Atlas project for the genotype and methylation data and the ENCODE project for the regulatory region data. This work was supported by the Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics and, in part, by the Norris Comprehensive Cancer Center core grant (P30CA014089) from NCI, the Trandisciplinary Research in Cancer of the Lung (TRICL) and the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network (U19CA148127). A.W., Z.W., W.Z. and A.H. were also funded by the NCI, NIH (HSN261200800001E). I.A.L.-O. and Z.B. were also funded by NIH grants (1 R01 HL114094, 1 P30 H101258, and R37HL062569-13), Whittier Foundation and Hastings Foundation. Z.B. was also funded by the Ralph Edgington Chair in Medicine. C.N.M. was funded by ACS/Canary postdoctoral fellowship (PFTED-10-207-01-SIED).

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=84921320301&partnerID=8YFLogxK

U2 - 10.1038/ncomms4365

DO - 10.1038/ncomms4365

M3 - Article

C2 - 24572595

AN - SCOPUS:84921320301

SN - 2041-1723

VL - 5

SP - 3365

JO - Nature communications

JF - Nature communications

M1 - 3365

ER -

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

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