Genome-wide meQTL mapping reveals genetic control of DNA methylation in colon cancer

Methylation quantitative trait loci (meQTLs) are essential for understanding the role of DNA methylation in the genetic susceptibility to colorectal cancer (CRC). However, studies of meQTLs in East Asians and at single base-pair resolution are relatively scarce. This study aims to characterize the genetic regulation of global DNA methylation and explore the underlying mechanisms of meQTLs contributing to CRC risk. To address this problem, we recruited 250 patients with colon cancer between 2007 and 2018 and isolated colon tumor samples with matched adjacent normal tissues. We conducted multi-omics profiling using whole-genome sequencing, whole-genome bisulfite sequencing, and RNA sequencing. Our analysis included methylome and transcriptome correlations (eQTMs) and local genetic regulation (meQTLs and eQTLs). To investigate the genetic impact of meQTLs on colon cancer, we systematically performed functional annotations, co-localization analyses, and mediation analyses. We identified a total of 48,429,542 cis-acting SNP-CpG associations in 553,834 meCpGs throughout the genome ( p < 2 × 10 −12 ). 63% of these CpGs linked to multiple lead meQTLs, suggesting pleiotropic genetic regulation of methylation. 16.8% of lead meQTLs were situated within the differentially methylated regions (DMRs) between tumoral and normal tissues, indicating that meQTLs may influence dysregulated methylation sites. Colocalization analysis revealed 14,104 CpG-Gene pairs that were likely to share causal variants, with meQTLs mediating 51% of the SNP effects on gene expression. Pathway analysis uncovered epigenetic regulation of translation, RNA polymerase, and DNA repair signaling pathways. Furthermore, our findings covered 86.6% of the previously identified CRC GWAS risk loci, and 40% of them were significantly co-localized. This study provides a comprehensive resource that comprises integrative genetic, epigenomic, and transcriptomic datasets on colon cancer, revealing co-regulation of methylation and gene expression at the single-base resolution across the genome, thereby enhancing the functional understanding of epigenetic and gene regulation underlying colon cancer.