Genetics, inflammation, and clinical outcomes in mental disorders: a personalized perspective
Genetics, inflammation, and clinical outcomes in mental disorders: a personalized perspective
This PhD thesis of Chenxu Zhao investigated the clinical, inflammatory, and genetic factors associated with cardiometabolic outcomes in individuals with mental health disorders, with a particular focus on shared genetic susceptibility. Using two well-characterized cohorts of patients with schizophrenia spectrum disorders (SSDs)and major depressive disorders (MDDs), the thesis examined how clinical symptoms, inflammation, psychotropic medication use, and polygenic risk jointly contribute to cardiometabolic risk.
I found that greater severity of psychiatric symptoms, especially cognitive impairment and negative symptoms, was associated with adverse cardiometabolic outcomes including higher body mass index, blood pressures, lipid and glucose biomarkers. These associations were largely independent of antipsychotic use, underscoring the intrinsic link between psychiatric illness and somatic health. In contrast, long-term antidepressant use was associated with multiple unfavorable cardiometabolic outcomes, highlighting medication-specific effects.
C-reactive protein showed consistent and robust associations with obesity-related traits, lipid profiles, and blood pressures. Genetic susceptibility to inflammation, particularly via polygenic risk for C-reactive protein, was modestly but consistently associated with metabolic outcomes among individuals with SSDs and MDDs.
Polygenic risk scores (PRS) for cardiometabolic traits were strongly associated with their corresponding phenotypes and explained a meaningful proportion of variance, with evidence of cross-trait genetic overlap, particularly for obesity-related traits. However, genetic risk alone accounted for only a limited share of cardiometabolic variability.
Overall, the findings demonstrate that cardiometabolic risk in mental health disorders arises from additive effects of genetic predisposition, inflammation, clinical symptom burden, and psychotropic medication. While current PRSes have limited clinical utility, they hold promise for future risk stratification and early intervention.