Introduction: Psychiatric disorders commonly co-occur with cardiometabolic disease, worsening clinical outcomes, quality of life, and life expectancy. This comorbidity may reflect shared biological pathways, or it may be mediated by behavioral changes and psychotropic treatments. Here we use polygenic risk scores (PRS) to investigate shared biology independent of diagnosis and medication exposure.

Methods: We tested associations between PRS for nine psychiatric disorders—schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, PTSD, ADHD, substance use disorder, autism spectrum disorder, and anorexia nervosa—and 249 circulating metabolites quantified using the Nightingale platform in 26,760 Mass General Brigham Biobank participants. To distinguish direct genetic effects from illness consequences, we conducted mediation analyses accounting for diagnosis and medication use.

Results:Major depression, PTSD, and ADHD PRS were associated with elevated triglycerides, reduced apolipoprotein A1, and increased glycoprotein acetyls (a marker of systemic inflammation). Autism PRS was associated with increased triglycerides and tyrosine. In contrast, schizophrenia and bipolar disorder PRS showed minimal metabolomic associations despite having the highest heritability. All associations remained consistent in medication-free and undiagnosed participants.

Conclusion: These findings suggest that shared lipid and inflammatory dysregulation contribute to psychiatric-cardiometabolic comorbidity, particularly for internalizing and neurodevelopmental disorders. The absence of metabolic associations for schizophrenia and bipolar disorder PRS suggests non-genetic factors may drive their cardiometabolic comorbidity.