Mapping genetic convergence across brain structure, mental health, and cardiometabolic disease

Abstract

Individuals with psychiatric disorders frequently experience comorbid cardiometabolic conditions, complicating treatment and worsening health outcomes. Both psychiatric and cardiometabolic disorders have been individually associated with alterations in brain structure. Yet, it remains unclear whether these associations stem from a shared genetic basis that underlies their frequent co-occurrence. We analyzed genome-wide association summary statistics from large international consortia of individuals of European ancestry, including psychiatric disorder GWAS with case–control sample sizes ranging from ~18,000 to ~158,000 cases, cardiometabolic disease GWAS with up to ~242,000 cases, and cortical morphology GWAS from UK Biobank comprising ~39,000 individuals. We applied complementary multivariate, causal, and mediation genetic analyses to disentangle genetic factors underlying brain alterations and comorbidity. Here we show that patterns of genetic overlap differ across disorders. Schizophrenia exhibits substantial polygenic overlap with cortical thickness and type 2 diabetes, despite low genetic correlation. In contrast, attention-deficit/hyperactivity disorder (ADHD) is more strongly correlated with cardiometabolic disease but shows limited overlap with cortical morphology. Notably, cortical surface area partly mediates the genetic association between ADHD and type 2 diabetes. Pathway analyses highlight metabolic stress processes in ADHD as well as neurodevelopmental and immune processes in schizophrenia. These findings indicate that psychiatric–cardiometabolic comorbidity arises through both shared and disorder-specific genetic pathways. This work clarifies the genetic architecture of multimorbidity and highlights opportunities for trait-targeted prevention strategies in psychiatry. Kopal et al. integrate large-scale genetic data to map the shared architecture across psychiatric disorders, cardiometabolic disease, and brain morphology. Their findings reveal divergent patterns: schizophrenia shows extensive overlap with cortical thickness and type 2 diabetes, whereas ADHD displays a metabolic-linked profile. Many people with psychiatric disorders also experience physical health problems, such as heart disease or diabetes. It remains unclear whether these links are due to shared genetic factors. In this study, we used large genetic datasets from hundreds of thousands of participants to investigate how psychiatric disorders, brain structure, and cardiometabolic diseases are genetically connected. We applied statistical methods to identify shared genetic influences and to explore whether one trait may partly influence another. We found that schizophrenia and ADHD show distinct genetic patterns: schizophrenia shares more genetic factors with brain structure and diabetes, while ADHD is more strongly linked to metabolic pathways. These findings highlight that different mental disorders may involve different biological routes, which could inform prevention and treatment strategies in the future.