Transcriptome-wide association studies (TWAS) can identify genes where genetically predicted gene expression is associated with disease risk, but translating those signals into therapeutic opportunities remains time-consuming, manual, and difficult to reproduce. We developed TRACE (TWAS-driven Repurposing through AI-assisted Curation of Evidence), a gene- and phenotype-agnostic computational pipeline that accepts a TWAS gene and effect-size direction, normalizes the gene symbol, retrieves FDA-approved drug-gene candidates from four online resources, collects related peer-reviewed literature from PubMed, and uses a fine-tuned biomedical language model to classify whether the literature supports a direct drug-gene relationship, the mechanism of action, and the direction of effect. The pipeline then compares the drug-derived direction with the direction implied by the TWAS effect estimate to rank candidate therapeutic pairs and flag potential drug safety concerns. The local classifier, built on BiomedBERT, was trained using pipeline-derived labels, BioCreative VI ChemProt gold-standard chemical-protein relation examples, and author-reviewed active-learning cases, reaching a held-out macro F1 of 0.809 across three simultaneous classification tasks. We validated the pipeline against a manually curated endometriosis gold standard of 43 drug-gene pairs spanning six TWAS-identified genes, developed through S-PrediXcan analysis of endometriosis GWAS summary statistics, manual querying of four drug-gene interaction databases for each gene, literature review of drug-gene mechanistic evidence, and Mendelian randomization validation of candidate pairs. External validation used two independently published genetically informed drug-repurposing studies in metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D). The pipeline recovered 90.7% of endometriosis pairs, 88.2% of MASLD pairs, and 92.9% of T2D pairs that were present in at least one queried database. Applied to 99 endometriosis-associated TWAS genes, the pipeline identified 1,089 FDA-approved drug-gene pairs, 32 candidate therapeutic pairs, and 77 potential safety concerns, including independent recovery of leuprolide acetate, an established endometriosis therapy. This framework provides a scalable, literature-grounded bridge from TWAS discovery to prioritized therapeutic hypotheses, while preserving uncertainty through manual-review flags and requiring downstream Mendelian randomization, electronic health record-based validation, and experimental follow-up before clinical interpretation.
C. O. Otieno, H. Seagle, A. Akerele et al.· medRxiv· 0 citations
BACKGROUND & AIMS
Genetic testing for Lynch and BRCA1/2-associated hereditary cancer syndromes is recommended in colon or pancreatic cancer patients, but their association with hepatocellular carcinoma (HCC) risk is unknown. We evaluated associations between rare germline variants in DNA-repair genes and HCC risk across ancestrally diverse cohorts.
METHODS
We analyzed whole exome (WES) and whole genome sequencing (WGS) data from 2,594 HCC cases and 290,547 cancer-free controls from diverse biobanks and cohorts: Penn Medicine BioBank, All of Us, Mayo Clinic, ESCALON, and the Million Veteran Program. Participants were classified into six population groups. We focused on six DNA-repair genes previously implicated in HCC: BRCA2, BRIP1, MSH6, PMS2, CHEK2, and FANCA. Gene-level burden analyses of rare predicted loss-of-function (pLoF) and damaging missense variants were performed in European and African populations, and across all six ancestry groups.
RESULTS
In the European population, MSH6, a Lynch syndrome-associated gene, had the strongest association with HCC, with a 2.75-fold increased HCC risk at 1% minor-allele frequency (MAF) (OR= 2.75 [1.50, 5.04], P=0.001, FDR q=0.02), while PMS2, showed a nominally significant association at the same MAF threshold (OR=1.90 [1.08, 3.34], P=0.03, FDR q=0.09). Combined analysis across all populations strengthened the MSH6 finding (OR=2.53 [1.43, 4.49], P=0.001, FDR q=0.01) at a MAF of 0.1%. A significant BRCA2 association was also observed in the combined analysis at a MAF of 0.1% (OR=2.26 [1.39, 3.67], P=0.001, FDR q=0.01).
CONCLUSIONS
Rare variants in MSH6 and BRCA2 are significantly associated with increased HCC risk, revealing a previously unconfirmed role for DNA repair genes in HCC susceptibility across ancestrally diverse populations. These findings may inform genetic risk stratification and surveillance strategies.
IMPACT AND IMPLICATIONS
Rare variants in MSH6 and BRCA2 genes are associated with 2.3 to 2.8-fold higher HCC risk. These findings may warrant further evaluation of liver cancer risk in individuals with MSH6-associated Lynch syndrome or BRCA2-associated hereditary cancer syndromes.
A. Garófalo, Perapa Chotiprasidhi, Josephine P. Johnson et al.· JHEP Reports· 0 citations
This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance and linking IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.
Biagio Di Lorenzo, L. Camargo Tavares, Cristian Díaz-Muñoz et al.· Gut· 0 citations