Abstract
Background
Cardiovascular disease (CVD) 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 CVD risk factors and after accounting for lifestyle and medication. It is not known if shared genetic aetiology is contributing to these cardiac variations.
Methods
Cardiac phenotypes were measured using MRI. First, we examined the relationship between polygenic risk score for schizophrenia (PRS-SCZ) and cardiac phenotype using principal component analysis (PCA) and regression. Second, we explored the relationship between PRS-SCZ and individual cardiac phenotypes using robust regression. Third, we repeated analyses with fibro-inflammatory pathway-specific PRS-SCZs. Fourth, we investigated genome-wide sharing of common variants between schizophrenia and cardiac phenotypes using linkage disequilibrium (LD) score regression.
Results
Data were available for 33,353 participants (nmale/nfemale = 16,238/17,115 (51% female); mean(SD) age= 55.10(7.39) years), all white British/Irish ethnicity); complete cardiac MRI data were available for 32,279 people. A model regressing PRS-SCZ onto the first 5 cardiac principal components (PCs) of the PCA was significant (F=5.09; P=0.0001). PC1 captured a pattern of increased cardiac volumes, reduced myocardial stiffness and reduced ejection fractions; there was a negative relationship between PRS-SCZ and PC1 (beta(SE)= -0.01(0.003); P=0.02). In keeping with the PCA results, for individual cardiac phonotypes, we observed negative associations between PRS-SCZ and indexed right ventricular end-systolic volume (beta(SE)= -0.14(0.04); P=0.001; PFDR=0.01), indexed right ventricular end-diastolic volume (beta(SE)= -0.17(0.08); P=0.03; PFDR=0.0975), and longitudinal peak diastolic strain rate (beta(SE)= -0.01(0.003); P=0.002; PFDR=0.01), and a positive association between PRS-SCZ and right ventricular ejection fraction (beta(SE)= 0.09(0.03); P=0.004; PFDR=0.02). Models examining TGFbeta and acute inflammation specific PRS-SCZ were significant. Using LD score regression, we observed genetic overlap with schizophrenia for right ventricular end-systolic volume (P=0.009) and right ventricular ejection fraction (P=0.008).
Conclusion
Higher PRS-SCZ is associated with smaller cardiac volumes, increased ejection fractions, and smaller absolute peak diastolic strain rates. TGFbeta and inflammatory pathways may be implicated, and there is evidence of genetic overlap for some cardiac phenotypes. Smaller 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 worsen cardiac outcomes.
Cardiovascular disease (CVD) 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 CVD risk factors and after accounting for lifestyle and medication. It is not known if shared genetic aetiology is contributing to these cardiac variations.
Methods
Cardiac phenotypes were measured using MRI. First, we examined the relationship between polygenic risk score for schizophrenia (PRS-SCZ) and cardiac phenotype using principal component analysis (PCA) and regression. Second, we explored the relationship between PRS-SCZ and individual cardiac phenotypes using robust regression. Third, we repeated analyses with fibro-inflammatory pathway-specific PRS-SCZs. Fourth, we investigated genome-wide sharing of common variants between schizophrenia and cardiac phenotypes using linkage disequilibrium (LD) score regression.
Results
Data were available for 33,353 participants (nmale/nfemale = 16,238/17,115 (51% female); mean(SD) age= 55.10(7.39) years), all white British/Irish ethnicity); complete cardiac MRI data were available for 32,279 people. A model regressing PRS-SCZ onto the first 5 cardiac principal components (PCs) of the PCA was significant (F=5.09; P=0.0001). PC1 captured a pattern of increased cardiac volumes, reduced myocardial stiffness and reduced ejection fractions; there was a negative relationship between PRS-SCZ and PC1 (beta(SE)= -0.01(0.003); P=0.02). In keeping with the PCA results, for individual cardiac phonotypes, we observed negative associations between PRS-SCZ and indexed right ventricular end-systolic volume (beta(SE)= -0.14(0.04); P=0.001; PFDR=0.01), indexed right ventricular end-diastolic volume (beta(SE)= -0.17(0.08); P=0.03; PFDR=0.0975), and longitudinal peak diastolic strain rate (beta(SE)= -0.01(0.003); P=0.002; PFDR=0.01), and a positive association between PRS-SCZ and right ventricular ejection fraction (beta(SE)= 0.09(0.03); P=0.004; PFDR=0.02). Models examining TGFbeta and acute inflammation specific PRS-SCZ were significant. Using LD score regression, we observed genetic overlap with schizophrenia for right ventricular end-systolic volume (P=0.009) and right ventricular ejection fraction (P=0.008).
Conclusion
Higher PRS-SCZ is associated with smaller cardiac volumes, increased ejection fractions, and smaller absolute peak diastolic strain rates. TGFbeta and inflammatory pathways may be implicated, and there is evidence of genetic overlap for some cardiac phenotypes. Smaller 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 worsen cardiac outcomes.
| Original language | English |
|---|---|
| Journal | The Lancet Psychiatry |
| Publication status | Accepted/In press - 18 Nov 2021 |
