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Effects of Schizophrenia, Bipolar Disorder, and Depression on Cardiopulmonary and Abdominal Organ Structure
Shengsi Chu1, Francesco Casanova1, Renu Bala1
1Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, United Kingdom.
Background:
People with severe mental illness (SMI) have shorter life expectancy, largely driven by physical health conditions. While lifestyle and psychotropic side effects contribute, peripheral organ dysregulation is intrinsic to SMI. Clarifying these effects could reveal novel therapeutic targets.
Methods:
Mendelian randomization (MR) was used to test the causal effects of genetic liability to schizophrenia, bipolar disorder, and major depressive disorder (MDD) on magnetic resonance imaging (MRI)-derived measures of peripheral organ structure and composition. Multivariable MR assessed lifestyle and metabolic mediators. One-sample MR and observational analyses in the UK Biobank (UKB) explored sex-specific effects. Two-sample MR used the largest genome-wide association study (GWAS) for schizophrenia (N = 175,799), bipolar disorder (N = 2,954,535), and MDD (N = 5,053,033). MRI-derived GWASs included up to 38,923 participants.
Results:
Genetic liability to all 3 SMIs associated with reduced peak diastolic strain rates, indicating impaired myocardial relaxation. Schizophrenia liability associated with smaller ventricular volumes, larger lung volumes, and higher liver iron levels. Bipolar disorder liability associated with lower right-sided cardiac volumes; higher left ventricular mass-to-volume ratio; and increased visceral, subcutaneous, and organ fat. MDD liability predominantly associated with greater abdominal and organ fat. Associations persisted after adjustment for body mass index, inflammation, insulin resistance, and smoking. One-sample MR in the UKB was directionally consistent and suggested sex-specific effects.
Conclusions:
SMI genetic liability exerts both shared and disorder-specific causal effects on peripheral organ structure, with myocardial stiffening (indicating poor cardiovascular prognosis) common to all, cardiopulmonary changes in schizophrenia, adipose-organ changes in MDD, and an intermediate phenotype in bipolar disorder. These cardiometabolic alterations support integrated screening and prevention strategies targeting cardiovascular and metabolic risk in SMI.
Insights
Genetic liability to severe mental illnesses (SMI) like schizophrenia, bipolar disorder, and major depressive disorder (MDD) causally impacts peripheral organs. This study reveals shared and specific organ changes, highlighting cardiovascular and metabolic risks in SMI.
Area of Science:
- Genetics and Psychiatry
- Cardiovascular Health
- Metabolic Disorders
Background:
- Severe mental illness (SMI) is linked to reduced life expectancy, primarily due to physical health issues.
- While lifestyle and medication side effects play a role, intrinsic peripheral organ dysregulation in SMI is increasingly recognized.
- Identifying these organ-specific effects may uncover novel therapeutic targets for SMI.
Purpose of the Study:
- To investigate the causal impact of genetic liability to schizophrenia, bipolar disorder, and major depressive disorder (MDD) on peripheral organ structure and composition.
- To explore potential lifestyle and metabolic mediators of these associations.
- To examine sex-specific effects of SMI genetic liability on organ structure.
Main Methods:
- Mendelian randomization (MR) analyses were employed to assess causal relationships.
- Two-sample MR utilized large genome-wide association study (GWAS) data for schizophrenia, bipolar disorder, and MDD.
- Magnetic resonance imaging (MRI)-derived GWAS data were used for peripheral organ measures, with one-sample MR and observational analyses in the UK Biobank (UKB) for sex-specific insights.
Main Results:
- Genetic liability to all three SMIs was associated with impaired myocardial relaxation (reduced peak diastolic strain rates).
- Schizophrenia liability showed associations with altered cardiac and lung volumes and increased liver iron.
- Bipolar disorder and MDD liabilities were linked to increased adiposity (visceral, subcutaneous, organ fat) and specific cardiac alterations.
Conclusions:
- Genetic liability for SMI has shared and disorder-specific causal effects on peripheral organ structure, including myocardial stiffening.
- Cardiopulmonary changes in schizophrenia and adipose-organ changes in MDD suggest distinct pathophysiological pathways.
- These findings underscore the need for integrated screening and prevention strategies for cardiovascular and metabolic risks in individuals with SMI.
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