This study used genomic structural equation modeling (SEM) on GWAS data from 5 psychiatric disorders (ADHD, anorexia nervosa, MDD, OCD, schizophrenia) and 3 insulin resistance (IR)-related conditions (metabolic syndrome, obesity, T2DM; N = 9,725–933,970) to map the shared genetic architecture of psychiatric-IR multimorbidity and identify biological pathways and repurposable drugs.
A latent 'Psych-IR' genetic factor was identified, with positive loadings for ADHD, MDD, and IR-related conditions and negative loadings for AN and OCD; multivariate GWAS of this factor yielded 150 associated loci and 366 genes (128 novel), with drug repurposing analysis flagging 6 candidates including memantine and rosiglitazone.
The sample sizes varied widely across contributing GWAS (N = 9,725–933,970), which may unevenly influence factor loadings; the latent factor approach captures shared variance but cannot establish causal direction; findings are largely restricted to populations of European ancestry, limiting generalizability.
Clinicians should be aware that ADHD and MDD share meaningful genetic overlap with metabolic conditions like obesity and T2DM, supporting routine metabolic screening in these patients. Repurposing candidates such as memantine and rosiglitazone warrant prospective study for psychiatric-metabolic comorbidity.
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