Cross-population genome-wide meta-analysis identifies pancreatic cancer susceptibility loci and etiologic pathways
TL;DR
A cross-population genome-wide association meta-analysis of 11 GWAS summary-statistic datasets comprises 20,120 pancreatic cancer cases and 1,446,192 controls genetically similar to European or East Asian reference populations refine the genetic architecture of pancreatic cancer and provide insights into candidate genes, biological pathways, and potential etiologic risk factors.
Abstract
Pancreatic cancer is a fatal malignancy influenced by genetic, metabolic, and lifestyle factors. We aimed to identify susceptibility loci and clarify associated genes, biological pathways, and potential etiologic factors. We performed a cross-population genome-wide association meta-analysis of 11 GWAS summary-statistic datasets comprising 20,120 pancreatic cancer cases and 1,446,192 controls genetically similar to European or East Asian reference populations. We integrated six gene-prioritization approaches, bulk-tissue and single-cell transcriptome-wide association studies, pathway enrichment, Mendelian randomization of modifiable factors and circulating proteins, and polygenic score and phenome-wide association analyses in UK Biobank. We identified 18 genome-wide significant loci, including four previously unreported loci, and prioritized one candidate gene at each locus. Transcriptome-wide association studies identified 46 genes associated with pancreatic cancer risk; ABO , PLEKHN1 , FBRSL1 , and KRT8 overlapped with genes identified by the gene-prioritization framework. Pathway enrichment implicated signal transduction, cell adhesion and migration, kinase-related pathways, and lipid metabolism. Mendelian randomization supported associations of genetically predicted fasting insulin, coffee consumption, obesity-related traits, and smoking-related traits with higher pancreatic cancer risk and moderate-to-vigorous physical activity with lower risk. Ten circulating proteins were associated with pancreatic cancer risk; eight—ABO, GRP, LGR4, CHST9, KRT18, IDUA, PCSK1, and FUT3—had strong colocalization support. Each one-standard-deviation increase in the polygenic score was associated with a 31% higher risk of incident pancreatic cancer (hazard ratio, 1.31; 95% confidence interval, 1.25–1.37), and phenome-wide association analyses identified 24 significant phenotypes. These findings refine the genetic architecture of pancreatic cancer and provide insights into candidate genes, biological pathways, and potential etiologic risk factors.