W16. LEVERAGING THE GENETICS OF MAJOR PSYCHIATRIC DISORDERS TO PRIORITIZE POTENTIAL DRUG THERAPIES AND TARGETS

• Published in: European neuropsychopharmacology 2024-10, Vol.87, p.108-109
• Main Authors: Parker, Nadine, Koch, Elise, Shadrin, Alexey, Fuhrer, Julian, Hindley, Guy, Stinson, Sara, Frei, Oleksandr, O'Connell, Kevin, Smeland, Olav, Andreassen, Ole
• Format: Article
• Language: English
• ISSN: 0924-977X
• DOI: 10.1016/j.euroneuro.2024.08.225

Psychiatric patients can experience inadequate response to drug therapies and adverse side effects, which may lead to poor compliance and potential relapse. Genetics has the potential to inform biologically relevant treatment options. Here, we combine methods which leverage the genetics of psychiatric disorders to prioritize potential therapeutic drugs and targets. We used GWAS summary statistics for four major psychiatric disorders (attention-deficit hyperactive disorder (ADHD), bipolar disorder (BIP), major depressive disorder (MDD), and schizophrenia (SCZ)) as well as diastolic blood pressure (DBP), as a comparator. Data from the Drug Gene Interaction database was used to generate drug-specific gene sets that were then used to conduct enrichment analyses using GSA-MiXeR with convergence of enrichment using MAGMA. We leveraged large transcriptomic and proteomic datasets sampled from the blood and brain tissue to identify potential drug targets using transcriptome/proteome wide association studies (TWAS/PWAS) and bi-directional Mendelian randomization (MR; using expression/protein quantitative trait loci). Colocalization analyses was also applied for all nominally significant TWAS/PWAS and MR associations. For each trait, we correlated effect estimates from the TWAS, PWAS, and MR analyses with effect estimates of drug induced gene expression changes. A negative correlation may be indicative of therapeutic potential. We then generate a prioritized list of drugs for each trait using the accumulating evidence across all analyses. A convergence of enrichment from GSA-MiXeR and MAGMA was observed for 9, 52, 72, and 149 drugs for ADHD, BIP, MDD, and SCZ, respectively. There was a significant overlap between BIP and SCZ enriched drugs (n=47, p=4.95e-21) but no significant overlap among the other psychiatric disorders. Several genes linked to enriched drugs were also represented among the drug target analyses using TWAS, PWAS, and MR. A few of these potential drug targets showed corroborating support from transcriptomic and proteomic sources and/or cross methodology support (TWAS/PWAS and MR). Colocalization was observed for many enriched and non-enriched potential drug targets. Additionally, a negative correlation between estriol-related gene expression and MDD PWAS associations in the brain was observed. Paliperidone, a commonly used antipsychotic, was the top ranked drug for SCZ after combining evidence across analyses. The top ranked drug for BIP was elpetrig