Effect of polygenic risk for schizophrenia on cardiac structure and function: a UK Biobank observational study

BACKGROUND: Cardiovascular disease is a major cause of excess mortality in people with schizophrenia. Several factors are responsible, including lifestyle and metabolic effects of antipsychotics. However, variations in cardiac structure and function are seen in people with schizophrenia in the absence of cardiovascular disease risk factors and after accounting for lifestyle and medication. Therefore, we aimed to explore whether shared genetic causes contribute to these cardiac variations. METHODS: For this observational study, we used data from the UK Biobank and included White British or Irish individuals without diagnosed schizophrenia with variable polygenic risk scores for the condition. To test the association between polygenic risk score for schizophrenia and cardiac phenotype, we used principal component analysis and regression. Robust regression was then used to explore the association between the polygenic risk score for schizophrenia and individual cardiac phenotypes. We repeated analyses with fibro-inflammatory pathway-specific polygenic risk scores for schizophrenia. Last, we investigated genome-wide sharing of common variants between schizophrenia and cardiac phenotypes using linkage disequilibrium score regression. The primary outcome was principal component regression. FINDINGS: =0·015). Models examining the transforming growth factor-β (TGF-β)-specific and acute inflammation-specific polygenic risk scores for schizophrenia found significant associations with the first five principal components (F=2·62, p=0·022; F=2·54, p=0·026). Using linkage disequilibrium score regression, we observed genetic overlap with schizophrenia for right ventricular end-systolic volume and right ventricular ejection fraction (p=0·0090, p=0·0077). INTERPRETATION: High polygenic risk scores for schizophrenia are associated with decreased cardiac volumes, increased ejection fractions, and decreased absolute peak diastolic strain rates. TGF-β and inflammatory pathways might be implicated, and there is evidence of genetic overlap for some cardiac phenotypes. Reduced absolute peak diastolic strain rates indicate increased myocardial stiffness and diastolic dysfunction, which increases risk of cardiac disease. Thus, genetic risk for schizophrenia is associated with cardiac structural changes that can worsen cardiac outcomes. Further work is required to determine whether these associations are specific to schizophrenia or are also seen in other psychiatric conditions.