Varicose veins of lower extremities (VVs) are a common multifactorial vascular disease. Genetic factors underlying VVs development remain largely unknown. Here we report the first large-scale study of VVs performed on a freely available genetic data of 408,455 European-ancestry individuals. We identified the 12 reliably associated loci that explain 13% of the SNP-based heritability, and prioritized the most likely causal genes CASZ1, PIEZO1, PPP3R1, EBF1, STIM2, HFE, GATA2, NFATC2, and SOX9. VVs-associated variants within these loci exhibited pleiotropic effects on several phenotypes including blood pressure/hypertension and blood cell traits. Gene set enrichment analysis revealed gene categories related to abnormal vasculogenesis. Genetic correlation analysis confirmed known epidemiological associations between VVs and deep venous thrombosis, weight, rough labor, and standing job, and found a genetic overlap with multiple traits that have not been previously suspected to share common genetic background with VVs. These traits included educational attainment, fluid intelligence and prospective memory scores, walking pace (negative correlation with VVs), smoking, height, number of operations, pain, and gonarthrosis (positive correlation with VVs). Finally, Mendelian randomization analysis provided evidence for causal effects of plasma levels of MICB and CD209 proteins, and anthropometric traits such as waist and hip circumference, height, weight, and both fat and fat-free mass. Our results provide novel insight into both VVs genetics and etiology. The revealed genes and proteins can be considered as good candidates for follow-up functional studies and might be of interest as potential drug targets.
Author summary Varicose veins of lower extremities (VVs) affect about 30% of adults in developed countries and cause both cosmetic and health problems. A strong body of evidence indicates that heredity plays an important role in the etiology of this condition. However, genetic basis of VVs remains poorly understood. Here, we present the results of the first large-scale genetic study for VVs. We identified genes which are the most likely involved in VVs pathogenesis. We show that VVs are correlated at a genetic level with numerous traits and phenotypes, including those already known from prior epidemiological studies (deep venous thrombosis, body mass index, standing job, etc.) as well as with those that have not been suspected to share common genetic background with VVs (fluid intelligence and prospective memory scores, smoking, walking pace, pain all over the body, and other traits). Finally, using genetic variants as instruments, we demonstrate direct causal effects of the traits related to anthropometry, such as height and weight, and plasma levels of immune-related proteins MICB and CD209. Our study provides novel insight into both VVs genetics and etiology. The revealed genes (CASZ1, PIEZO1, PPP3R1, EBF1, STIM2, HFE, GATA2, NFATC2, and SOX9) and proteins (MICB and CD209) can be considered as good candidates for follow-up functional studies and might be of interest as potential drug targets.