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Genetic Regulation of DNA Methylation Yields Novel Discoveries in GWAS of Colorectal Cancer.
Pubmed ID
35247911 (View this publication on the PubMed website)
Digital Object Identifier
Cancer Epidemiol Biomarkers Prev. 2022 May 4; Volume 31 (Issue 5): Pages 1068-1076
Barfield R , Huyghe JR , Lemire M , Dong X , Su YR , Brezina S , Buchanan DD , Figueiredo JC , Gallinger S , Giannakis M , Gsur A , Gunter MJ , Hampel H , Harrison TA , Hopper JL , Hudson TJ , Li CI , Moreno V , Newcomb PA , Pai RK , more Pharoah PDP , Phipps AI , Qu C , Steinfelder RS , Sun W , Win AK , Zaidi SH , Campbell PT , Peters U , Hsu L
  • Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • Neurosciences and Mental Health Program, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Biostatistics Unit, Kaiser Permanente Washington Health Research Institute, Seattle, Washington.
  • Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
  • Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
  • Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
  • International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, Lyon, France. more
  • Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona.
  • Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Department of Epidemiology, School of Public Health and Institute of Health and Environment, Seoul National University, Seoul, South Korea.
  • Department of Population Science, American Cancer Society, Atlanta, Georgia.

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.

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