Polygenic risk of Major Depressive Disorder as a risk factor for Venous Thromboembolism.

Major depessive disorder (MDD), bipolar disorder (BD) and schizophrenia (SCZ) are accompanied by an increased risk of cardiovascular diseases including venous thromboembolism (VTE). Reasons for this are complex, and include obesity, smoking and use of hormone and psychotropic medications. Genetic studies increasingly provide evidence of shared genetic risk of psychiatric and cardiometabolic illness. This study aimed to determine whether genetic predisposition to MDD, BD or SCZ was associated with an increased risk of VTE. Genetic correlations using the largest genome-wide genetic meta-analyses summary statistics for MDD, BD and SCZ (Psychiatric Genetics Consortium) and a recent genome-wide genetic meta-analysis of VTE (INVENT consortium) demonstrated a positive association between VTE and MDD but not BD or SCZ. The same summary statistics were used to construct polygenic risk scores for MDD, BD and SCZ in UK Biobank participants of self-reported white British ancestry. These were assessed for impact on self-reported VTE risk (10786 cases, 285124 controls), using logistic regression, in sex-specific and sex-combined analyses. We identified significant positive associations between polygenic risk for MDD and risk of VTE in men, women and sex-combined analyses, independent of known risk factors. Secondary analyses demonstrated that this association was not driven by those with lifetime experience of mental illness. Meta-analyses of individual data from six additional independent cohorts replicated the sex-combined association. This report provides evidence for shared biological mechanisms leading to MDD and VTE, and suggests that, in the absence of genetic data, family history for MDD might be considered when assessing risk of VTE.