The multivariate genetic architecture of psychiatric and insulin resistance multimorbidity.

Psychiatric disorders frequently co-occur with insulin resistance (IR)-related conditions, including obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS). While genetic correlations have been reported, the genetics underlying this multimorbidity remains underexplored. Here, we investigate the joint genetic architecture of psychiatric-IR multimorbidity and explore links with the brain, tissue-specific gene expression, potential underlying biological mechanisms, and repurposable drugs. Genomic structural equation modeling (SEM) was applied to genome-wide association studies (GWAS) from five psychiatric disorders (attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), schizophrenia) and three IR-related conditions (MetS, obesity, T2DM) (N = 9725-933,970) previously showing pairwise genetic correlations. Factor analyses identified a latent genetic factor (Psych-IR factor) capturing shared genetics across psychiatric disorders (excluding schizophrenia) and IR-related conditions. Positive loadings were observed for ADHD, MDD, and IR-related conditions and negative loadings for AN and OCD. This factor showed genetic correlations with temporal, occipital, and total brain surface areas. A multivariate GWAS of the Psych-IR factor identified 150 associated loci and 366 genes (128 novel). Gene-set associations included insulin binding and Notch-signaling pathways, while gene-property analyses implicated the cerebellum, brain cortex, and pituitary gland, notably during prenatal development. Transcriptome-wide SEM (T-SEM) assessed tissue-specific gene expression associations and identified 499 genes (191 novel), including immune-related genes within the major histocompatibility complex (MHC) region. Drug repurposing analysis suggested six therapeutic candidates, including memantine and rosiglitazone. Enrichment of prioritized genes highlighted the chr16p11.2 region, BDNF-signaling, and lipid metabolism pathways. These findings advance understanding of the genetic and biological mechanisms underpinning psychiatric-IR multimorbidity, informing future research on precision medicine initiatives.