@article{24df9b47907e4885a2ad833a29ce42c1,
title = "Genetic Regulation of DNA Methylation Yields Novel Discoveries in GWAS of Colorectal Cancer",
abstract = "Background: Colorectal cancer has a strong epigenetic component that is accompanied by frequent DNA methylation (DNAm) alterations in addition to heritable genetic risk. It is of interest to understand the interrelationship of germline genetics, DNAm, and colorectal cancer risk. Methods: We performed a genome-wide methylation quantitative trait locus (meQTL) analysis in 1,355 people, assessing the pairwise associations between genetic variants and lymphocytes methylation data. In addition, we used penalized regression with cis-genetic variants ± 1 Mb of methylation to identify genome-wide heritable DNAm. We evaluated the association of genetically predicted methylation with colorectal cancer risk based on genome-wide association studies (GWAS) of over 125,000 cases and controls using the multivariate sMiST as well as univariately via examination of marginal association with colorectal cancer risk. Results: Of the 142 known colorectal cancer GWAS loci, 47 were identified as meQTLs. We identified four novel colorectal cancer–associated loci (NID2, ATXN10, KLHDC10, and CEP41) that reside over 1 Mb outside of known colorectal cancer loci and 10 secondary signals within 1 Mb of known loci. Conclusions: Leveraging information of DNAm regulation into genetic association of colorectal cancer risk reveals novel pathways in colorectal cancer tumorigenesis. Our summary statistics-based framework sMiST provides a powerful approach by combining information from the effect through methylation and residual direct effects of the meQTLs on disease risk. Further validation and functional follow-up of these novel pathways are needed. Impact: Using genotype, DNAm, and GWAS, we identified four new colorectal cancer risk loci. We studied the landscape of genetic regulation of DNAm via single-SNP and multi-SNP meQTL analyses.",
author = "Richard Barfield and Huyghe, {Jeroen R.} and Mathieu Lemire and Xinyuan Dong and Su, {Yu Ru} and Stefanie Brezina and Buchanan, {Daniel D.} and Figueiredo, {Jane C.} and Steven Gallinger and Marios Giannakis and Andrea Gsur and Gunter, {Marc J.} and Heather Hampel and Harrison, {Tabitha A.} and Hopper, {John L.} and Hudson, {Thomas J.} and Li, {Christopher I.} and Victor Moreno and Newcomb, {Polly A.} and Pai, {Rish K.} and Pharoah, {Paul D.P.} and Phipps, {Amanda I.} and Conghui Qu and Steinfelder, {Robert S.} and Wei Sun and Win, {Aung Ko} and Zaidi, {Syed H.} and Campbell, {Peter T.} and Ulrike Peters and Li Hsu",
note = "Funding Information: The authors thank the participants across all studies. In addition, we thank the reviewers for valuable feedback. This project was a part of Richard Barfield{\textquoteright}s postdoctoral work at Fred Hutch. L. Hsu was partially funded by the NIH/NCI grant R01 CA189532. U. Peters was supported by the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): NCI, NIH, U.S. Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045, and R01 CA201407). Analyses were run on the Fred Hutch cluster, which is part of the Scientific Computing Infrastructure funded by ORIP grant S10OD028685. A full list of study-specific acknowledgments is provided in the Supplementary Data. Funding Information: M. Giannakis reports grants from Bristol-Myers Squibb, Merck, Servier, and Janssen outside the submitted work. H. Hampel reports other support from Invitae, Genome Medical, Promega, and GI OnDemand outside the submitted work. T.J. Hudson reports being currently employed by AbbVie. T.J. Hudson reports that contributions to this manuscript are related to former position at the Ontario Institute for Cancer Research; AbbVie has no connection to the manuscript. V. Moreno reports grants from the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government, Instituto de Salud Carlos III, cofunded by FEDER Funds—a Way to Build Europe, grants from Spanish Association Against Cancer (AECC) Scientific Foundation, and Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) during the conduct of the study. R.K. Pai reports personal fees from Alimentiv, Inc., Allergan, Eli Lilly, AbbVie, and PathAI outside the submitted work. P.D. Pharoah reports grants from Cancer Research UK during the conduct of the study. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright}2022 American Association for Cancer Research results from large-scale GWAS studies, and summary statistics-based methods, it is now feasible to study these relationships. In this paper, we examine the impact of genetic variants on DNAm and utilize this information to study the association of methylation quantitative trait loci (meQTL) with colorectal cancer risk.",
year = "2022",
month = may,
doi = "10.1158/1055-9965.EPI-21-0724",
language = "English (US)",
volume = "31",
pages = "1068--1076",
journal = "Cancer Epidemiology Biomarkers and Prevention",
issn = "1055-9965",
publisher = "American Association for Cancer Research Inc.",
number = "5",
}
