Transcriptome-Wide Structural Equation Modeling of 13 Major Psychiatric Disorders for Cross-Disorder Risk and Drug Repurposing
Year: 2023
Type: article
Abstract: Importance: Psychiatric disorders display high levels of comorbidity and genetic overlap, necessitating multivariate approaches for parsing convergent and divergent psychiatric risk pathways. Identifying gene expression patterns underlying cross-disorder risk also stands to propel drug discovery and repurposing in the face of rising levels of polypharmacy. Objective: To identify gene expression patterns underlying genetic convergence and divergence across psychiatric disorders along with existing pharmacological interventions that target these genes. Design, Setting, and Participants: This genomic study applied a multivariate transcriptomic method, transcriptome-wide structural equation modeling (T-SEM), to investigate gene expression patterns associated with 5 genomic factors indexing shared risk across 13 major psychiatric disorders. Follow-up tests, including overlap with gene sets for other outcomes and phenome-wide association studies, were conducted to better characterize T-SEM results. The Broad Institute Connectivity Map Drug Repurposing Database and Drug-Gene Interaction Database public databases of drug-gene pairs were used to identify drugs that could be repurposed to target genes found to be associated with cross-disorder risk. Data were collected from database inception up to February 20, 2023. Main Outcomes and Measures: Gene expression patterns associated with genomic factors or disorder-specific risk and existing drugs that target these genes. Results: In total, T-SEM identified 466 genes whose expression was significantly associated (z ≥ 5.02) with genomic factors and 36 genes with disorder-specific effects. Most associated genes were found for a thought disorders factor, defined by bipolar disorder and schizophrenia. Several existing pharmacological interventions were identified that could be repurposed to target genes whose expression was associated with the thought disorders factor or a transdiagnostic p factor defined by all 13 disorders. Conclusions and Relevance: The findings from this study shed light on patterns of gene expression associated with genetic overlap and uniqueness across psychiatric disorders. Future versions of the multivariate drug repurposing framework outlined here have the potential to identify novel pharmacological interventions for increasingly common, comorbid psychiatric presentations.
Source: JAMA Psychiatry
Institutions: University of Colorado Boulder, Vanderbilt University Medical Center, Broad Institute, Northwell Health, Massachusetts General Hospital, Institute of Mental Health, Zucker Hillside Hospital, Stanley Center for Psychiatric Research, Genome Institute of Singapore, Central South University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: American Heart Association, Tommy Fuss Fund, Vanderbilt University, Vanderbilt University Medical Center, Georgia Clinical and Translational Science Alliance, National Institutes of Health, Medical Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Dissecting the Multivariate Genetic Architecture of Psychiatric Diseases, Pharmacogenomics of Arrhythmia Therapy, G1531600799, G1766209448, Large-Scale Genomic Analysis of Aging-Related Cognitive Change Prior to Dementia Onset, G2103760183, Understanding the genetic risk underlying racial disparities in uterine fibroids, G2615776415, G2683268942, G3272238124, Improving Prediction of Drug Action, G3395468139, G3619590958, G364208108, G3791753988, G3938985443, G4049315607, Automated Storage and Retrieval of Biological Systems, G4395870004, G4410787187, G5199261032, UK Biobank (core renewal), G560889077, G5679716143, G5717004637, Genetic Epidemiology of Multiple Sclerosis, G6589054092, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, VESPA: Vanderbilt Electronic Systems for Pharmacogenomic Assessment, G7163342664, The Vanderbilt Institute for Clinical and Translational Research (VICTR), Vanderbilt Genome Electronic Records Project, PsycheMERGE: Leveraging electronic health records and genomics for mental health research, eMERGE Phase IV Clinical Center at Mass General Brigham, G8098630230, Epidemiologic Architecture for Genes Linked to Environment (EAGLE), G8332127685, Center on Aging and Population Sciences, Vanderbilt Institute for Clinical and Translational Research (VICTR)
OpenAlex ID: W4380576732