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 Of 33 353 individuals recruited, 32 279 participants had complete cardiac MRI data and were included in the analysis, of whom 16 625 (51 center dot 5%) were female and 15 654 (48 center dot 5%) were male. 1074 participants were excluded on the basis of incomplete cardiac MRI data (for all phenotypes).A model regressing polygenic risk scores for schizophrenia onto the first five cardiac principal components of the principal components analysis was significant (F=5 center dot 09; p=0 center dot 00012). Principal component 1 captured a pattern of increased cardiac volumes, increased absolute peak diastolic strain rates, and reduced ejection fractions; polygenic risk scores for schizophrenia and principal component 1 were negatively associated (13=-0 center dot 01 [SE 0 center dot 003]; p=0 center dot 017). Similar to the principal component analysis results, for individual cardiac phenotypes, we observed negative associations between polygenic risk scores for schizophrenia and indexed right ventricular end -systolic volume (13=-0 center dot 14 [0 center dot 04]; p=0 center dot 0013, pFDR=0 center dot 015), indexed right ventricular end -diastolic volume (13=-0 center dot 17 [0 center dot 08]); p=0 center dot 025; pFDR=0 center dot 082), and absolute longitudinal peak diastolic strain rates (13=-0 center dot 01 [0 center dot 003]; p=0 center dot 0024, pFDR=0 center dot 015), and a positive association between polygenic risk scores for schizophrenia and right ventricular ejection fraction (13=0 center dot 09 [0 center dot 03]; p=0 center dot 0041, pFDR=0 center dot 015). Models examining the transforming growth factor -13 (TGF-13)-specific and acute inflammation -specific polygenic risk scores for schizophrenia found significant associations with the first five principal components (F=2 center dot 62, p=0 center dot 022; F=2 center dot 54, p=0 center dot 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 center dot 0090, p=0 center dot 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-13 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. Funding National Institute for Health Research, Maudsley Charity, Wellcome Trust, Medical Research Council, Academy of Medical Sciences, Edmond J Safra Foundation, British Heart Foundation Copyright (c) 2023 Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.