Abstract
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.
Highlights
Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Laboratory of Recombination and Segregation Analysis, Institute of Cytology and Genetics, Knomics LLC, Skolkovo Innovation Center, Moscow, Russia
Our objectives were to (1) identify genetic loci reliably associated with Varicose veins of lower extremities (VVs) risk and prioritize the genes that account for the revealed associations, (2) elucidate pleiotropic effects of identified loci, (3) investigate genetic overlap between VVs and other complex traits, (4) gain etiological insights and explore cause-and-effect relationships by means of Mendelian randomization analysis
To be able to perform a replication, we extracted the UK Biobank data not covered by this project by means of reverse meta-analysis of two overlapping datasets: genetic association data provided by the Gene ATLAS database and the genome-wide association study (GWAS) data supplied by the
Summary
Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Laboratory of Recombination and Segregation Analysis, Institute of Cytology and Genetics, Knomics LLC, Skolkovo Innovation Center, Moscow, Russia. Dr Yakov Tsepilov, Laboratory of Recombination and Segregation Analysis, Institute of Cytology and Genetics, 10 Lavrentjev Avenue, Novosibirsk 630090, Russia. VVs can be found in different parts of the body, but most commonly occur in the lower extremities. Prevalence estimates of this condition vary across ethnic groups ranging from 2-4% in the Northern group of the Cook Islands to 50-60% in some countries of the Western world[1]. VVs not related to the post-thrombotic syndrome or venous malformations are defined as primary VVs
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