ArticleHuman mutation2026
From Germline Variants to Tumor Outcome: GWAS-Based Functional Genomics Prioritizes Colorectal Cancer Susceptibility Genes and Links
Article in Human mutation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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1 citing paper in PubMed.
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18 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Introduction: Genome-wide association studies (GWAS) have identified over 200 germline risk loci for colorectal cancer (CRC), yet the causal variants and genes behind most GWAS signals remain unknown and the link between inherited risk and tumor outcome is largely unexplored. Connecting germline single nucleotide polymorphisms (SNPs) to gene expression through expression quantitative trait loci (eQTL) and to clinical outcome is needed to interpret this inherited risk. Methods: We combined CRC GWAS summary data (73,149 cases and 112,467 controls of European ancestry) with GTEx v8 eQTL from colon sigmoid, colon transverse, small intestine terminal ileum, and whole blood, integrating causal transcriptome-wide association study (cTWAS) with SuSiE fine-mapping, Bayesian colocalization, MAGMA SNP-to-gene analysis, and AlphaGenome variant-effect prediction. Prioritized proteins were assessed by western blot. Four experimentally selected regulatory variants were genotyped in HCT116, SW480, RKO, and NCM460 cells; genotype-protein associations were tested across cell-line means, and cis-regulatory effects were assessed by allele-specific expression (ASE) and reference-versus-alternate dual-luciferase assays. Prognostic relevance was evaluated in TCGA colorectal tumors. Results: cTWAS identified seven genes with posterior inclusion probability (PIP) > 0.50, and colocalization across 78 gene-tissue pairs revealed 20 associations with PP.H4 > 0.80. Four genes showed convergent evidence: SMAD9 (PIP = 0.916, PP.H4 = 0.981), MAP3K2 (PIP = 0.762, PP.H4 = 0.827), FADS1 (PIP = 0.632, PP.H4 = 0.942), and ACTR1B (PIP = 0.566, PP.H4 = 0.994). All four proteins were reduced in CRC cells. Alt-allele dosage was inversely associated with SMAD9 (Pearson r = -0.985, BH-adjusted Conclusions: Integrating statistical genetics, regulatory prediction, and locus-directed experiments prioritized SMAD9, MAP3K2, FADS1, and ACTR1B as CRC susceptibility genes. Functional evidence was strongest and most directionally coherent for SMAD9, demonstrated allele-specific but context-dependent regulation at FADS1, and placed experimental bounds on the proposed MAP3K2 and ACTR1B mechanisms.
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