The multivariate genetic architecture of psychiatric and insulin resistance multimorbidity

作者：Nina Roth Mota, Giuseppe Fanelli, Izel Erdogan, Marieke Klein, Emma Sprooten, Ábel Fóthi, I. Hyun Ruisch, Geert Poelmans, Kazi Asraful Alam, Jan Haavik, Theresa Wimberley, Martina Arenella, Csaba Barta, Willemijn J. Jansen, Alessandro Serretti, Chiara Fabbri, Barbara Franke, Janita Bralten · 发表于：European Neuropsychopharmacology · 年份：2026 · DOI：10.1016/j.euroneuro.2026.112906 · 被引用次数：2 · 研究领域：Genetic Associations and Epidemiology

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...