Association of Genetic Liability to Psychiatric Disorders with Peripheral Metabolic Dysregulation

Individuals with psychiatric disorders face elevated cardiometabolic risk which is linked to increased mortality. The extent to which this reflects shared pathogenesis or the downstream effects of illness and treatment remains poorly understood.

To characterize the direct pleiotropic effects of psychiatric genetic liability on circulating metabolites and aggregate cardiometabolic risk, independent of psychiatric diagnosis and psychotropic medication use.

Cross-sectional analysis of Mass General Brigham Biobank participants with metabolomic profiling, genomic data, and linked electronic health records.

Genetic liability to nine psychiatric disorders quantified using polygenic risk scores (PRS): attention deficit/hyperactivity disorder (ADHD), anorexia nervosa (ANO), anxiety disorder (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), PTSD, schizophrenia (SCZ), and substance use disorder (SUD).

249 circulating metabolites and four metabolomic risk scores (MRS) for type 2 diabetes, myocardial infarction, ischemic stroke, and vascular dementia. PRS-metabolite associations were estimated using nested models adjusting for lifetime psychiatric diagnosis and psychotropic medication use.

Across 25,290 participants, we identified 604 significant PRS-metabolite associations (Bonferroni p< 1.36 × 10 ^-4 ), of which 89% persisted after adjustment for lifetime diagnosis and medication use, suggesting that the direct genetic effects on metabolism are largely independent of illness or treatment. PRS for MDD, PTSD, and ADHD showed the most extensive dysregulation, with a transdiagnostic pattern of elevated lipids and systemic inflammation, specifically triglycerides (β = 0.04 to 0.05, all p< 4.4 ×10 ^-13 ) and glycoprotein acetyls (β = 0.05, all p< 2.2 ×10 ^-16 ). Notably, PRS for SCZ and BD showed minimal metabolite dysregulation despite having the strongest association with their target diagnoses. PRS for MDD, PTSD, ADHD, and SUD were associated with increased MRS across cardiometabolic conditions (β = 0.03 to 0.08, all p< 2.1 ×10 ^-4 ). Sensitivity analyses controlling for BMI or excluding participants without any psychiatric history (N: 21,305 and 11,150, respectively) showed a similar pattern.

Psychiatric genetic liability is associated with systemic metabolic dysregulation independent of illness onset or treatment, supporting a partially pleiotropic basis for psychiatric-cardiometabolic comorbidity.

Question: Does genetic liability to psychiatric disorders influence peripheral metabolism independent of psychiatric diagnosis and treatment?Findings: In 25,290 participants, polygenic scores for major depressive disorder, posttraumatic stress disorder, and attention deficit hyperactivity disorder showed widespread associations with metabolic dysregulation, such as elevated triglycerides and systemic inflammation, which persisted after adjusting for diagnosis and medication use. Polygenic scores for schizophrenia and bipolar disorder showed minimal metabolite associations despite their well-established cardiometabolic burden.Meaning: Shared genetic pathways partially underlie psychiatric and cardiometabolic comorbidity, implicating transdiagnostic biomarker profiles.