Hypothesis-free analysis of deep vein thrombosis aetiology: a Mendelian randomization study

Background: Deep vein thrombosis (DVT) is the formation of a thrombus/clot in the deep veins, when part of this clot breaks off it can travel to the lungs, resulting in pulmonary embolism. These two conditions together are known as venous thromboembolism (VTE), a leading cause of death and disability worldwide. Despite the prevalence of VTE, we do not fully understand what causes it and it is often overlooked as a major public health problem. Confirming and identifying risk factors associated with DVT is likely to lead to a reduction in the incidence, morbidity and mortality of VTE especially where these risk factors are modifiable. We can do this, by exploiting the availability of summary genetic data from genome-wide association studies (GWAS) of numerous phenotypes, including DVT, which permits hypothesis-free causal inference. Objectives: To identify novel risk factors for DVT and to assess the causality of factors previously shown to be associated with DVT. Methods: Two-sample Mendelian randomization (MR) was performed using summarised genetic data. Inverse variance weighted (IVW) estimates were calculated and validated by additional methods more robust to horizontal pleiotropy (MR Egger, simple mode, weighted mode, and weighted median). Bidirectional and heterogeneity sensitivity analyses were performed to further evaluate our findings. Results: Forty-seven exposures passed an exposure-exposure correlation-adjusted Bonferroni P-value threshold (5.43E-05). These included previously hypothesised risk factors for DVT (e.g. body mass index, varicose veins, height, hyperthyroidism) and novel associations (e.g. prospective memory, basal metabolic rate). Conclusion: Our analyses confirmed causal associations of risk factors previously associated with DVT and highlighted several novel risk factors for the disease. Our study demonstrates the utility of using a hypothesis free Mendelian randomization approach for the identification of novel disease risk factors.