Protocol Title: Leveraging multi-omic data integration for in silico compound prioritization.
This project seeks to leverage large-scale robust evidence across omic domains to produce a catalog of biological targets and candidate compounds for future drug repurposing, aimed at improving the effectiveness and trajectory of treatment for alcohol and substance use disorders (ASUDs) and/or posttraumatic stress disorder (PTSD). This catalog will be made possible by collecting existing multi-omic results, performing integrated analyses, and systematically searching target-compound databases. The catalog will include summaries of the supporting evidence for the target or compound’s inclusion and ranking. This actionable, interpretable, and annotated resource will be made available to the drug repurposing community who are the intended recipients of PASA-funded preclinical and clinical trials. The results will also provide an unbiased distillation of evidence across multiple domains which will aid in the evaluation of future proposals received by PASA. To produce such a resource, we propose the following aims.
Aim 1: Identify genetic loci influencing common versus specific risk to PTSD, AUD, and OUD:
1a) Collect genome-wide association studies (GWAS) meta-analyses
1b) Leverage cross-disorder genetic correlations to disentangle pleiotropy
Aim 2: Identify gene expression modules enriched for ASUD and PTSD liability:
2a) Collect gene expression studies of post-mortem human brains
2b) Perform cross-omic network analysis **
Aim 3: Identify and prioritize therapeutic compounds: There is a growing array of resources and tools for identifying compounds that target individual genes or proteins as well as those impacting biological networks. Using these resources and the novel findings generated in aims 1 and 2, this project will:
3a) Rank all genes in human genome
3b) Identify compounds targeting high ranked genes and networks
3c) Produce a catalog of genes and compounds