Cancer Epidemiol Biomarkers Prev. 2022 Mar 3:cebp.0724.2021. doi: 10.1158/1055-9965.EPI-21-0724. Online ahead of print.
ABSTRACT
BACKGROUND: Colorectal cancer (CRC) 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 CRC risk.
METHODS: We performed a genome-wide methylation quantitative trait locus (meQTL) analysis in 1355 people, assessing the pairwise associations between genetic variants and lymphocytes methylation data. In addition, we used penalized regression with cis-genetic variants +/- 1Mb of methylation to identify genome-wide heritable DNAm. We evaluated the association of genetically predicted methylation with CRC risk based on GWAS of over 125,000 cases and controls using the multivariate sMiST as well as univariately via examination of marginal association with CRC risk.
RESULTS: Of the 142 known CRC genome-wide association studies (GWAS) loci, 47 were identified as meQTLs. We identified 4 novel CRC associated loci (NID2, ATXN10, KLHDC10 and CEP41) that reside over 1Mb outside of known CRC loci and 10 secondary signals within 1Mb of known loci.
CONCLUSIONS: Leveraging information of DNAm regulation into genetic association of CRC risk reveals novel pathways in CRC 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, DNA methylation, GWAS, we identified four new CRC risk loci. We studied the landscape of genetic regulation of DNA methylation via single-SNP and multi-SNP meQTL analyses.
PMID:35247911 | DOI:10.1158/1055-9965.EPI-21-0724
