Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk.
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ICR Authors
Authors
Law, PJ
Studd, J
Smith, J
Vijayakrishnan, J
Harris, BT
Mandelia, M
Mills, C
Dunlop, MG
Houlston, RS
Studd, J
Smith, J
Vijayakrishnan, J
Harris, BT
Mandelia, M
Mills, C
Dunlop, MG
Houlston, RS
Document Type
Journal Article
Date
2024-10-01
Date Accepted
2024-08-07
Abstract
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.
Citation
Nature Genetics, 2024, 56 (10), pp. 2104 - 2111
Source Title
Nature Genetics
Publisher
NATURE PORTFOLIO
ISSN
1061-4036
eISSN
1546-1718
Collections
Research Team
Cancer Genomics