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 reflect a shared genetic basis that also contributes to their frequent co-occurrence. Here we analyzed genome-wide association summary statistics for psychiatric disorders, cardiometabolic disease, and brain morphology using complementary genetic approaches to disentangle genetic factors underlying brain alterations and comorbidity. Our results highlighted differences in patterns of genetic overlap across disorders. Schizophrenia showed substantial polygenic overlap with cortical thickness and type 2 diabetes, despite low genetic correlation. In contrast, ADHD was more genetically correlated with cardiometabolic disease but showed limited overlap with cortical morphology. Mediation analysis suggested that cortical surface area may partly mediate the genetic link between ADHD and type 2 diabetes. Pathway enrichment highlighted metabolic stress in ADHD and neurodevelopmental and immune processes in schizophrenia. These findings suggest that psychiatric-cardiometabolic comorbidity arises through both shared and disorder-specific genetic pathways, clarifying the genetic architecture of multimorbidity and informing trait-targeted prevention strategies in psychiatry.

OAA has received speaker's honorarium from Lundbeck, Janssen, Otsuka, and Sunovion and is a consultant to Cortechs.ai. and Precision Health. AMD was a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is also a member of the Scientific Advisory Board of Human Longevity, Inc. (HLI), and the Mohn Medical Imaging and Visualization Centre in Bergen, Norway. He receives funding through a research agreement with General Electric Healthcare (GEHC). The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. All other authors report no potential conflicts of interest.

The authors were funded by the Research Council of Norway (296030, 324252, 324499, 326813, 334920, 351751); the South-Eastern Norway Regional Health Authority (2020060); European Union's Horizon 2020 Research and Innovation Programme (Grant No. 847776; CoMorMent and Grant No. 964874; RealMent); EU's Horizon Psych-STRATA project (#101057454); National Institutes of Health (NIH; U24DA041123; R01AG076838; U24DA055330; and OT2HL161847). JK was supported by a Marie Sklodowska-Curie Postdoctoral Fellowship under the European Union's Horizon Europe research and innovation programme (Grant Agreement No.101150746).

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All GWAS summary statistics used in this study are publicly available through their respective consortia or original publications.

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All GWAS summary statistics used in this study are publicly available through their respective consortia or original publications.