Dissecting Gene Regulatory Contributions to Opioid Use Disorder Risk

About This Grant

PROJECT SUMMARY Opioid use disorder (OUD) is a devastating neuropsychiatric condition and a major public health crisis in the United States, with fentanyl, a synthetic opioid 100 times more potent than morphine, driving a sharp rise in overdose deaths. Although many individuals are exposed to opioids, only a subset develop OUD. This is especially evident in family studies, which estimate OUD heritability at 40–60%, suggesting that genetics shape individual risk. Genome-wide association studies (GWAS) have identified common variants associated with OUD. Over 90% of these GWAS variants are located in non-coding regions of the genome—regions that are often regulatory and whose activity varies by context (e.g., cell type, tissue, exposure). Postmortem studies have been invaluable in detecting dysregulated genes in the brains of OUD donors. However, these studies cannot distinguish inherited regulatory effects from changes caused by opioid exposure or the disease itself. For this reason, the genes and specific regulatory non-coding variants that contribute to OUD risk remain unknown. This project addresses this gap by identifying the genes that causally mediate OUD risk and by experimentally testing the effects of associated regulatory variants in human neurons exposed to fentanyl or vehicle. In Aim 1, I will apply a multi-tissue integrative Mendelian randomization framework (mintMR) to determine how inherited variation influences gene regulation (expression and DNA methylation) across human brain regions, allowing me to identify causal genes and the tissues in which they act. In Aim 2, I will use Massively Parallel Reporter Assays (MPRA) to functionally test thousands of fine-mapped non-coding variants associated with OUD, integrating these results with enhancer–gene interaction models to identify the putative target genes of regulatory variants. Together, these studies will identify the genes and brain regions that causally contribute to OUD risk and determine which non-coding OUD-associated variants affect gene regulation in unexposed and opioid- exposed human neurons. Through this project, I will receive rigorous training in computational biology, functional genomics, stem cell neuroscience, and addiction biology, preparing me for a career leading research on the molecular mechanisms of OUD.