Pathway and network embedding methods for prioritizing psychiatric drugs

• Published in: Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing Vol. 25; p. 671
• Main Authors: Pershad, Yash, Guo, Margaret, Altman, Russ B
• Format: Journal Article
• Language: English
• Published: United States 2020
• Subjects: Computational Biology; Depressive Disorder, Major - genetics; Drug Therapy; Gene Expression; Gene Regulatory Networks; Genome-Wide Association Study; Genomics; Humans; Pharmaceutical Preparations; Protein Interaction Maps - genetics; Schizophrenia - drug therapy; Schizophrenia - genetics
• ISSN: 2335-6936

One in five Americans experience mental illness, and roughly 75% of psychiatric prescriptions do not successfully treat the patient's condition. Extensive evidence implicates genetic factors and signaling disruption in the pathophysiology of these diseases. Changes in transcription often underlie this molecular pathway dysregulation; individual patient transcriptional data can improve the efficacy of diagnosis and treatment. Recent large-scale genomic studies have uncovered shared genetic modules across multiple psychiatric disorders - providing an opportunity for an integrated multi-disease approach for diagnosis. Moreover, network-based models informed by gene expression can represent pathological biological mechanisms and suggest new genes for diagnosis and treatment. Here, we use patient gene expression data from multiple studies to classify psychiatric diseases, integrate knowledge from expert-curated databases and publicly available experimental data to create augmented disease-specific gene sets, and use these to recommend disease-relevant drugs. From Gene Expression Omnibus, we extract expression data from 145 cases of schizophrenia, 82 cases of bipolar disorder, 190 cases of major depressive disorder, and 307 shared controls. We use pathway-based approaches to predict psychiatric disease diagnosis with a random forest model (78% accuracy) and derive important features to augment available drug and disease signatures. Using protein-protein-interaction networks and embedding-based methods, we build a pipeline to prioritize treatments for psychiatric diseases that achieves a 3.4-fold improvement over a background model. Thus, we demonstrate that gene-expression-derived pathway features can diagnose psychiatric diseases and that molecular insights derived from this classification task can inform treatment prioritization for psychiatric diseases.