Genetic associations with pulmonary embolism among those with a deep vein thrombosis: the INVENT Consortium.

Venous thromboembolism (VTE) includes deep vein thrombosis (DVT) and pulmonary embolism (PE), which often originate from DVT and can be fatal. Identifying causal genetic factors that alter risk of PE among those with a presumed DVT. Using a case-only design of VTE, we conducted meta-analyses of genome-wide association studies (GWAS) in the INVENT Consortium. Among participants diagnosed with VTE, each study identified those who had a clinically reported PE, with or without a clinically reported DVT; those remaining had isolated DVT. Logistic regression models (PE as outcome compared with isolated DVT) were used for variant discovery and replication analyses. A polygenic risk score (PRS) was created from the GWAS findings. Transcriptome-wide association study (TWAS) analyses were conducted using the GWAS discovery estimates. Our discovery and replication analyses included 126,316 individuals with a VTE across 29 studies: 54,389 who had a PE and the remaining 71,927 who had an isolated DVT. Five variants reached genome-wide significance (p<5x10-8) in discovery, 4 of which replicated: F5 rs6025 (FV Leiden), odds ratio (OR) 0.66; FGG rs2066864, OR 1.08; F11 rs4253417, OR 1.07; and SLC12A2-DT rs3749748, OR 0.92. Each standard deviation increase in the PRS was associated with risk (OR 1.05; 95% CI: 1.003-1.094). TWAS identified genetic associations with FGG, SLC12A2-DT, and CDHR4 transcripts. Although the overall risk for VTE is strongly heritable, our findings support the hypothesis that PE in the setting of a presumed DVT is regulated by genetics, although the overall effect appears modest.