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. 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.