Novel susceptibility genes for varicose veins revealed by a cross-tissue transcriptome-wide association study

ObjectiveTo identify susceptibility genes associated with varicose veins (VVs) using a cross-tissue transcriptome-wide association study (TWAS) framework.MethodsWe performed a cross-tissue TWAS by integrating GWAS data from the FinnGen R12 dataset (38,467 VVs cases and 432,223 controls of European ancestry) with eQTL data from GTEx V8. The initial analysis was conducted using the Unified Test for Molecular Signatures (UTMOST), and subsequent validation incorporated multiple complementary methods, including Functional Summary-based Imputation (FUSION), Conditional and Joint Association Analysis (COJO), Fine-mapping Of CaUsal gene Sets (FOCUS), and Multi-marker Analysis of Genomic Annotation (MAGMA). Mendelian randomization (MR) and colocalization analyses were performed to explore potential genetically supported associations between candidate genes and VVs. Finally, Western blotting (WB) was conducted in venous tissue samples collected from patients undergoing surgery for VVs to provide preliminary experimental validation.ResultsThis cross-tissue TWAS analysis identified four genes (MAP3K2, PDK1, TMEM87B, and POLR1B) as susceptibility genes associated with VVs risk. MR indicated that PDK1, TMEM87B, and POLR1B may be associated with the development of VVs. Colocalization analysis suggested that POLR1B was the primary candidate gene, showing strong colocalization with VVs in whole blood (PPH4 = 0.987), and preliminary WB results suggested that the protein level of POLR1B was significantly elevated in varicose tissue.ConclusionOur findings identify POLR1B as a promising candidate susceptibility gene potentially associated with VVs risk, providing a basis for future mechanistic and translational studies.