Exploring the Relationship Between Schizophrenia and Cardiovascular Disease: A Genetic Correlation and Multivariable Mendelian Randomization Study

Abstract

Individuals with schizophrenia have a reduced life-expectancy compared to the general population, largely due to an increased risk of cardiovascular disease (CVD). Clinical and epidemiological studies have been unable to unravel the nature of this relationship. We obtained summary-data of genome-wide-association studies of schizophrenia (N = 130 644), heart failure (N = 977 323), coronary artery disease (N = 332 477), systolic and diastolic blood pressure (N = 757 601), heart rate variability (N = 46 952), QT interval (N = 103 331), early repolarization and dilated cardiomyopathy ECG patterns (N = 63 700). We computed genetic correlations and conducted bi-directional Mendelian randomization (MR) to assess causality. With multivariable MR, we investigated whether causal effects were mediated by smoking, body mass index, physical activity, lipid levels, or type 2 diabetes. Genetic correlations between schizophrenia and CVD were close to zero (-0.02-0.04). There was evidence that liability to schizophrenia causally increases heart failure risk. This effect remained consistent with multivariable MR. There was also evidence that liability to schizophrenia increases early repolarization pattern, largely mediated by BMI and lipids. Finally, there was evidence that liability to schizophrenia increases heart rate variability, a direction of effect contrasting clinical studies. There was weak evidence that higher systolic blood pressure increases schizophrenia risk. Our finding that liability to schizophrenia increases heart failure is consistent with the notion that schizophrenia involves a systemic dysregulation of the body with detrimental effects on the heart. To decrease cardiovascular mortality among individuals with schizophrenia, priority should lie with optimal treatment in early stages of psychosis.

Keywords: QT interval; causality; coronary artery disease; dilated cardiomyopathy; early repolarization; heart rate variability.

Fig. 1.

Mendelian randomization (MR). (A) MR relies on 3 assumptions; the genetic variants in the instrument must (1) associate robustly with the exposure (e.g. schizophrenia), (2) be independent of confounders, and (3) not directly affect the outcome (e.g. heart failure), except through their effect on the exposure. (B) Multivariable MR allows an additional variable, besides the main exposure. We tested whether key health behaviours mediate the effect of schizophrenia on cardiovascular disease. E.g., if the inclusion of smoking (considerable) decreases the direct effect of schizophrenia on heart failure, it implies that smoking mediates the relationship.

Fig. 2.

Forest plots of multivariable Mendelian randomization (MR) analyses of liability to schizophrenia on heart failure (A), heart rate variability (B), and early repolarization (C), showing the direct effect of liability to schizophrenia on the respective outcomes. Each health behaviour was added in a separate analysis. Lifetime smoking and physical activity could not be added for C, because there was considerable sample overlap.