Proteome-wide Mendelian randomization and colocalization analysis identifying candidate proteins associated with gastric cancer risk

Abstract:

Background and Aims Gastric cancer lacks highly effective and widely applicable biomarkers for early detection. Circulating proteins are measurable molecular intermediates with potential biological and clinical relevance. This study aimed to systematically evaluate the genetic associations between circulating plasma proteins and gastric cancer risk and to prioritize proteins with convergent genetic evidence.Methods A two-sample Mendelian randomization (MR) analysis was conducted using pQTL summary statistics for 4 907 plasma proteins as exposures and FinnGen Release 12 gastric cancer GWAS data as the outcome. Candidate signals were further evaluated using summary-data-based Mendelian randomization (SMR)/heterogeneity in dependent instruments (HEIDI) analysis and Bayesian colocalization analysis to assess the probability of shared causal variants between protein and gastric cancer signals. Independent European gastric cancer GWAS data were subsequently used for external validation and meta-analysis. TCGA-STAD, GTEx, and GEPIA2 datasets were further used to investigate tissue expression, prognostic relevance, and associated biological processes of the prioritized candidate gene.Results The MR screen identified 84 candidate proteins associated with gastric cancer risk, including 36 risk-increasing and 48 protective signals. SMR analysis further prioritized 11 positive proteins. Bayesian colocalization analysis showed that HGF had the strongest evidence for a shared causal variant (PP.H4=0.792). External GWAS validation and meta-analysis further supported the association between genetically predicted higher circulating HGF levels and increased gastric cancer risk (OR=1.224, 95% CI=1.070-1.401, P=0.003). Transcriptomic analyses demonstrated that HGF was upregulated in gastric cancer tissues, and high HGF expression was associated with poorer overall survival and disease-free survival. GSEA indicated that HGF-related genes were mainly enriched in extracellular matrix remodeling, angiogenesis, and immune regulatory processes.Conclusion This study constructed a genetic prioritization landscape of circulating proteins associated with gastric cancer risk and provided convergent genetic evidence supporting HGF as a prioritized gastric cancer-related candidate protein. These findings offer molecular clues for future risk stratification, mechanistic investigation, and clinical validation in gastric cancer.