ArticleBritish journal of cancer2025
Isoform-level analyses of 6 cancers uncover extensive genetic risk mechanisms undetected at the gene-level.
Article in British journal of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed.
- Single-cell full-length transcriptome of human lung reveals genetic effects on isoform regulation beyond gene-level expression.bioRxiv : the preprint server for biology · 2026Article
- Improving isoform-level eQTL and integrative genetic analyses of breast cancer risk with long-read RNA transcript assemblies.bioRxiv : the preprint server for biology · 2026Article
- Integrative screening identifies functional variants and VNTRs underlying GWAS signals at the 5p15.33 multi-cancer susceptibility locus.medRxiv : the preprint server for health sciences · 2026Article
- Cell-type aware transcriptome-wide association study of mammographic density phenotypes.medRxiv : the preprint server for health sciences · 2025Article
- mRNA Isoforms and Variants in Health and Disease.International journal of molecular sciences · 2025Review
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Abstract
backgroundIntegrating genome-wide association study (GWAS) and transcriptomic datasets can identify mediators for genetic risk of cancer. Traditional methods often are insufficient as they rely on total gene expression measures and overlook alternative splicing, which generates different transcript-isoforms with potentially distinct effects.
methodsWe integrate multi-tissue isoform expression data from the Genotype Tissue-Expression Project with GWAS summary statistics (all N > ~20,000 cases) to identify isoform- and gene-level associations with six cancers (breast, endometrial, colorectal, lung, ovarian, prostate) and six related cancer subtype classifications (N = 12 total).
resultsDirectly modeling isoforms using transcriptome-wide association studies (isoTWAS) significantly improves discovery of genetic associations compared to gene-level approaches, identifying 164% more significant associations (6163 vs. 2336) with isoTWAS-prioritized genes enriched 4-fold for evolutionarily-constrained genes. isoTWAS tags transcriptomic associations at 52% more independent GWAS loci across the six cancers. Isoform expression mediates an estimated 63% greater proportion of cancer risk SNP heritability compared to gene expression. We highlight several isoTWAS associations that demonstrate GWAS colocalization at the isoform level but not at the gene level, including CLPTM1L (lung cancer), LAMC1 (colorectal), and BABAM1 (breast).
conclusionThese results underscore the importance of modeling isoforms to maximize discovery of genetic risk mechanisms for cancers.
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