Genetics of mood instability and risk of cardiovascular diseases: A univariable and multivariable Mendelian randomization study

Background: Cardiovascular diseases (CVDs) are significant contributors to global disability and mortality. In addition to traditional cardiovascular risk factors, emerging evidence has suggested that mental health plays a critical role as a risk factor for CVDs. The present study aimed to determine the associations between mood instability and CVDs using Mendelian randomization (MR) analysis.Methods: As instrumental variables, we used 62 independent single-nucleotide polymorphisms associated with mood instability at the genome-wide significance threshold in the UK Biobank. Summary-level data for seven CVDs were obtained from the publicly available genome-wide association studies. The estimates were pooled by using a random-effects inverse-variance weighted method. The results were further validated in sensitivity analysis where different MR methods were compared.Results: After correcting for multiple testing, our analysis revealed that genetic liability to mood instability was associated with increased odds of six cardiovascular diseases, including deep vein thrombosis (odds ratio (OR) 1.21; confidence interval (CI) 1.03-1.42), pulmonary embolism (OR 1.42; 95 % CI 1.09-1.85), heart failure (OR 1.20; 95 % CI 1.09-1.32), arterial hypertension (OR 1.22; 95 % CI 1.11-1.34), myocardial infarction (OR 1.25; 95 % CI 1.11-1.40), and coronary artery disease (OR 1.25; 95 % CI 1.13-1.39). Further, the genetic liability to mood instability was associated with HDL cholesterol, triglycerides, body mass index, smoking, and depression. In multivariable MR models, the association between genetic liability to mood instability and CVDs remained independent from those cardiovascular risk factors.Conclusion: The present MR study suggests potential causal associations of genetic liability to mood instability with increased risk of a broad range of CVDs.