Effects of Schizophrenia, Bipolar Disorder, and Depression on Cardiopulmonary and Abdominal Organ Structure

Background People with severe mental illness (SMI) have shorter life expectancy, largely driven by physical health conditions. Whilst lifestyle and psychotropic side-effects contribute, peripheral organ dysregulation is intrinsic to SMI. Clarifying these effects could reveal novel therapeutic targets. Methods Mendelian randomisation (MR) was used to test the causal effects of genetic liability to schizophrenia, bipolar disorder, and major depressive disorder (MDD) on magnetic resonance imaging-derived measures of peripheral organ structure and composition. Multivariable MR assessed lifestyle and metabolic mediators. One-sample MR and observational analyses in UK Biobank (UKB) explored sex-specific effects. Two-sample MR used the largest GWAS for schizophrenia (n=175,799), bipolar disorder (n=2,954,535) and MDD (n=5,053,033). MRI-derived GWAS included up to 38,923 participants. Results Genetic liability to all three SMIs associated with reduced PDSR, indicating impaired myocardial relaxation. Schizophrenia liability associated with smaller ventricular volumes, larger lung volumes, and higher liver iron. 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 BMI, inflammation, insulin resistance, and smoking. One-sample MR in UKB were 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. Plain language summary People with severe mental illness (such as schizophrenia, bipolar disorder, and depression) often die earlier, mainly due to physical health problems. This study used genetic methods to test whether these conditions directly affect body organs. We found that all three conditions are linked to reduced heart function, suggesting stiffer heart muscle. Schizophrenia mainly affected the heart and lungs, while bipolar disorder and depression were linked to increased body and organ fat. These findings suggest that physical health monitoring and early prevention should be a routine part of care for people with severe mental illness.