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INTRODUCTION: Deep vein thrombosis (DVT) is a complex disease, where 60 % of risk is due to genetic factors, such as the Factor V Leiden (FVL) variant. DVT is either asymptomatic or manifests with unspecific symptoms and, if left untreated, DVT leads to severe complications. The impact is dramatic and currently, there is still a research gap in DVT prevention. We characterized the genetic contribution and stratified individuals based on genetic makeup to evaluate if it favorably impacts risk prediction.

METHODS: In the UK Biobank (UKB), we performed gene-based association tests using exome sequencing data, as well as a genome-wide association study. We also constructed polygenic risk scores (PRS) in a subset of the cohort (Number of cases = 8231; Number of controls = 276,360) and calculated the impact on the prediction capacity of the PRS in a non-overlapping part of the cohort (Number of cases = 4342; Number of controls = 142,822). We generated additional PRSs that excluded the known causative variants.

RESULTS: We discovered and replicated a novel common variant (rs11604583) near the region where are located the TRIM51 and LRRC55 genes and identified a novel rare variant (rs187725533) located near the CREB3L1 gene, associated with 2.5-fold higher risk of DVT. In one of the PRS models constructed, the top decile of risk is associated with 3.4-fold increased risk, an effect that is 2.3-fold when excluding FVL carriers. In the top PRS decile, the cumulative risk of DVT at the age of 80 years is 10 % for FVL carriers, contraposed to 5 % for non-carriers. The population attributable fractions of having a high polygenic risk on the rate of DVT was estimated to be around 20 % in our cohort.

CONCLUSION: Individuals with a high polygenic risk of DVT, and not only carriers of well-studied variants such as FVL, may benefit from prevention strategies.