Identifying compounds to treat opiate use disorder by leveraging multi-omic data integration and multiple drug repurposing databases

Genes influencing opioid use disorder (OUD) biology have been identified via genome-wide association studies (GWAS), gene expression, and network analyses. These discoveries provide opportunities to identifying existing compounds targeting these genes for drug repurposing studies. However, systematically integrating discovery results and identifying relevant available pharmacotherapies for OUD repurposing studies is challenging. To address this, we’ve constructed a framework that leverages existing results and drug databases to identify candidate pharmacotherapies. For this study, two independent OUD related meta-analyses were used including a GWAS and a differential gene expression (DGE) study of post-mortem human brain. Protein-Protein Interaction (PPI) sub-networks enriched for GWAS risk loci were identified via network analyses. Drug databases Pharos, Open Targets, Therapeutic Target Database (TTD), and DrugBank were queried for clinical status and target selectivity. Cross-omic and drug query results were then integrated to identify candidate compounds. GWAS and DGE analyses revealed 3 and 335 target genes (FDR q<0.05), respectively, while network analysis detected 70 genes in 22 enriched PPI networks. Four selection strategies were implemented, which yielded between 72 and 676 genes with statistically significant support and 110 to 683 drugs targeting these genes, respectively. After filtering out less specific compounds or those targeting well-established psychiatric-related receptors ( OPRM1 and DRD2 ), between 2 and 329 approved drugs remained across the four strategies. By leveraging multiple lines of biological evidence and resources, we identified many FDA approved drugs that target genes associated with OUD. This approach a) allows high-throughput querying of OUD-related genes, b) detects OUD-related genes and compounds not identified using a single domain or resource, and c) produces a succinct summary of FDA approved compounds eligible for efficient expert review. Identifying larger pools of candidate pharmacotherapies and summarizing the supporting evidence bridges the gap between discovery and drug repurposing studies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Alcohol and Substance Use Research Program under Award No. W81XWH1820044 (PASA 2). Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All contributing cohorts obtained necessary patient/participant consent and appropriate institutional IRB approval received. Meta-analyses of genetic data from Gaddis et al. is approved under RTI International IRB review (IRB ID: CR00000710 for 14107). The details of the IRB/oversight body that provided approval or exemption to the datasets from Carter et. are given below: Corradin O, Sallari R, Hoang AT, Kassim BS, Ben Hutta G, Cuoto L, et al. Convergence of case specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose. Mol Psychiatry. 2022 Apr;27(4):215870. Mendez EF, Wei H, Hu R, Stertz L, Fries GR, Wu X, et al. Angiogenic Gene Networks are Dysregulated in Opioid Use Disorder: Evidence from MultiOmics and Imaging of Postmortem Human Brain. Mol Psychiatry. 2021 Dec;26(12):780312. Seney ML, Kim SM, Glausier JR, Hildebrand MA, Xue X, Zong W, et al. Transcriptional Alterations in Dorsolateral Prefrontal Cortex and Nucleus Accumbens Implicate Neuroinflammation and Synaptic Remodeling in Opioid Use Disorder. Biol Psychiatry. 2021 Oct 15;90(8):55062. Sosnowski DW, Jaffe AE, Tao R, Deep Soboslay A, Shu C, Sabunciyan S, et al. Differential expression of NPAS4 in the dorsolateral prefrontal cortex following opioid overdose. Drug Alcohol Depend Rep. 2022 Jun 1;3:100040. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.