O21: GENOME-WIDE ASSOCIATION STUDY OF VARICOSE VEINS IN 810,625 INDIVIDUALS IDENTIFIES 45 GENETIC RISK LOCI

Abstract Introduction Varicose veins (VV) impact a third of the UK adult population; 10% patients develop lipodermatosclerosis and ulceration. VV often requires surgical management, however, there is high-risk recurrence. complex disease, where genetic non-genetic components contribute to overall phenotypic expression. The architecture poorly understood; we aimed uncover its basis. Method We conducted hitherto largest genome-wide association study VV. In stage one, using Biobank, compared 22,473 379,183 controls. two, replication meta-analysis were performed in an independent cohort 113,041 cases 295,928 controls from 23&Me (California, USA). In-silico analysis was FUMA, MAGMA, XGR. Result 109 significant (P≤ 5×10-8) loci identified 45 which successfully replicated cohort. Twenty-seven have not been previously reported. FUMA positionally-mapped 128 genes at loci, with 84 having combined annotation-dependent depletion score (CADD) >12.37, suggesting functional, deleterious variants. MAGMA implicated pathways involved cardiovascular system development (P=1.57×10-08) tube morphogenesis (P=9.35×10-08). Furthermore, XGR revealed enriched downstream signalling naive CD8+ T cells (P=0.0017), encoding structural core extracellular glycoproteins (both P=0.007). Conclusion variants conferring risk VV, provide insights into disease biology. Implicated are vascular development, immune cell activity matrix function, new targets for therapeutic development. Take-home message Unravelling varicose may facilitate our understanding guide approaches.