Veterans Affairs Boston Healthcare System, Boston, MA, USA.
Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Nat Genet. 2019 Nov;51(11):1574-1579. doi: 10.1038/s41588-019-0519-3. Epub 2019 Nov 1.
Venous thromboembolism is a significant cause of mortality, 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.
静脉血栓栓塞是一个重要的死亡原因，但它的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，对大约 1300 万个 DNA 序列变体进行了静脉血栓栓塞（26066 例病例和 624053 例对照）的关联测试，并对两项研究进行了荟萃分析，然后对多达 17672 例静脉血栓栓塞病例和 167295 例对照进行了独立复制。我们确定了 22 个以前未知的位点，使与静脉血栓栓塞相关的位点总数达到 33 个，并随后对这些关联进行了精细映射。我们开发了一个用于静脉血栓栓塞的全基因组多基因风险评分，该评分可以识别出 5%的人群具有与已确定的因子 V 莱顿 p.R506Q 和凝血酶原 G20210A 突变携带者相同的静脉血栓栓塞发病风险。我们的数据为静脉血栓栓塞的遗传流行病学提供了机制上的见解，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。
