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Daniel J. Rader

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Open access Aug 2026

Multi-ancestry sequencing analysis in 293,141 participants identifies predisposition DNA repair genes associated with HCC risk.

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. · 0 citations
Open access Jul 2026

The landscape of plasma proteomic links to human organ imaging

Plasma protein levels provide important insights into human disease, yet a comprehensive assessment of plasma proteomics across organs is lacking. Using large-scale multimodal data from the UK Biobank, we integrate plasma proteomics with organ imaging to map their phenotypic and genetic links, analyzing 2923 proteins and 1051 imaging traits across multiple organs. We uncover 5067 phenotypic protein-imaging associations, identifying both organ-specific and organ-shared proteomic relations, along with enriched protein-protein interaction networks and biological pathways. Sensitivity analyses suggest that these associations are not substantially influenced by the median 10.18-year interval between plasma sampling and imaging visits. We also map key protein predictors of organ structures and show the stratification capability of plasma protein-based prediction models. Furthermore, we identify 8116 putative causal protein-imaging links. Imaging-associated protein components show enrichment across diverse complex diseases. Our study shows that integrating plasma proteomics with multi-organ imaging provides a comprehensive pan-organ imaging-proteomics map and reveals molecular pathways linking circulating proteins to human organ biology. Fan and colleagues present a study where they map links between plasma proteins and imaging traits across multiple human organs, revealing organ-specific and cross-organ protein signatures, predictive biomarkers, and genetic evidence supporting causal protein-imaging relationships.

Zirui Fan, J. Chirinos, Xiaochen Yang et al. · 0 citations
Open access Jul 2026

Cross-definition GWAS of IBS in 2.8 million individuals reveals cardiometabolic and triglyceride-linked mechanisms

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. · 0 citations