Divergent gene expression patterns in alcohol and opioid use disorders lead to consistent alterations in functional networks within the Dorsolateral Prefrontal Cortex

ABSTRACT Substance Use Disorders (SUDs) manifest as persistent drug-seeking behavior despite adverse consequences, with Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) representing prevalent forms associated with significant mortality rates and economic burdens. The co-occurrence of AUD and OUD is common, necessitating a deeper comprehension of their intricate interactions. While the causal link between these disorders remains elusive, shared genetic factors are hypothesized. Leveraging public datasets, we employed genomic and transcriptomic analyses to explore conserved and distinct molecular pathways within the dorsolateral prefrontal cortex associated with AUD and OUD. Our findings unveil modest transcriptomic overlap at the gene level between the two disorders but substantial convergence on shared biological pathways. Notably, these pathways predominantly involve inflammatory processes, synaptic plasticity, and key intracellular signaling regulators. Integration of transcriptomic data with the latest genome-wide association studies (GWAS) for problematic alcohol use (PAU) and OUD not only corroborated our transcriptomic findings but also confirmed the limited shared heritability between the disorders. Overall, our study indicates that while alcohol and opioids induce diverse transcriptional alterations at the gene level, they converge on select biological pathways, offering promising avenues for novel therapeutic targets aimed at addressing both disorders simultaneously. Competing Interest Statement Dr. Kranzler is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, Enthion Pharmaceuticals, and Clearmind Medicine. A consultant to Sobrera Pharmaceuticals. The recipient of research funding and medication supplies for an investigator-initiated study from Alkermes. A member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics. And a holder of U.S. patent 10,900,082 titled Genotype-guided dosing of opioid agonists issued 26 January 2021.