Philip J. Law, James Studd, James Smith, Jayaram Vijayakrishnan, Bradley T. Harris et al.
Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer–gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment.
Philip J. Law, James Studd, James Smith, Jayaram Vijayakrishnan, Bradley T. Harris, Maria Mandelia, Charlie Mills, Malcolm G. Dunlop, Richard S. Houlston. Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk. 2024-09-16. https://doi.org/10.1038/s41588-024-01900-w
Lentiviral MPRA of 8,880 GWAS-selected colorectal cancer variants represented by 201-bp genomic probes with reference and alternate alleles in both strands. SW403 colorectal cancer cells were transduced and barcode abundance in DNA and cDNA was used to estimate alternate-versus-reference regulatory activity; the released ST4 table contains the 275-variant union significant in at least one assayed cell line.
Lentiviral MPRA of 8,880 GWAS-selected colorectal cancer variants represented by 201-bp genomic probes with reference and alternate alleles in both strands. HT29 colorectal cancer cells were transduced and barcode abundance in DNA and cDNA was used to estimate alternate-versus-reference regulatory activity; the released ST4 table contains the 275-variant union significant in at least one assayed cell line.
Lentiviral MPRA of 8,880 GWAS-selected colorectal cancer variants represented by 201-bp genomic probes with reference and alternate alleles in both strands. HCEC-1CT immortalized normal colon crypt cells were transduced and barcode abundance in DNA and cDNA was used to estimate alternate-versus-reference regulatory activity; the released ST4 table contains the 275-variant union significant in at least one assayed cell line.
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