Varicose veins of lower extremities: Insights from the first large-scale genetic study

PLoS Genet. 2019 Apr 18;15(4):e1008110. doi: 10.1371/journal.pgen.1008110. eCollection 2019 Apr.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Computational Biology / methods
  • Disease Susceptibility*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Lower Extremity / blood supply*
  • Lower Extremity / pathology*
  • Polymorphism, Single Nucleotide
  • Quantitative Trait, Heritable
  • Varicose Veins / etiology*
  • Varicose Veins / pathology*


  • Biomarkers

Grants and funding

The work of ASSh was supported by the Russian Science Foundation [Project No 17-75-20223]. The work of YAT and SZS were supported by the Federal Agency of Scientific Organizations via the Institute of Cytology and Genetics [Project No 0324-2019-0040]. The development of the GWAS-MAP platform was supported by grants from the Russian Ministry of Science and Education under the 5-100 Excellence Programme, British Council's Institutional Links Programme for Novosibirsk State University and University of Edinburgh (Project reference No IL4277322879), and by PolyKnomics BV. We thank Maatschap PolyOmica for providing free of charge access to computational services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.