Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.

中文翻译：

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静脉血栓栓塞的全基因组关联分析确定了新的风险位点和与动脉血管疾病的遗传重叠。

静脉血栓栓塞是导致死亡的重要原因 1，但其遗传决定因素尚未完全确定。我们在百万退伍军人计划和英国生物库中进行了一项发现全基因组关联研究，测试了大约 1300 万个 DNA 序列变体与静脉血栓栓塞的关联（26,066 例病例和 624,053 例对照），并对这两项研究进行荟萃分析，然后进行独立复制多达 17,672 例静脉血栓栓塞病例和 167,295 例对照。我们确定了 22 个以前未知的基因座，使静脉血栓栓塞相关基因座的总数达到 33 个，并随后对这些关联进行了精细映射。我们开发了一个全基因组的静脉血栓栓塞多基因风险评分，该评分确定了 5% 的人群与已确定的因子 V Leiden p.R506Q 和凝血酶原 G20210A 突变的携带者具有同等的静脉血栓栓塞风险。我们的数据为静脉血栓栓塞的遗传流行病学提供了机制见解，并表明静脉和动脉心血管疾病之间的重叠比以前认为的要大。