Differential Expression ofNPAS4in the Dorsolateral Prefrontal Cortex Following Acute Opioid Intoxication

Background and Aims The physical, emotional, and social impacts of opioid abuse are well known; although preclinical models reveal the neurobiological pathways altered through opioid abuse, comprehensive assessments of gene expression in human brain samples are lacking. The goals of the present study were to compare gene expression in the prefrontal cortex between brain samples of individuals who died of acute opioid intoxication and group-matched controls, and to test if differential gene expression was enriched in gene sets related to opioid use. Design Cross-sectional study using human brains donated to the Lieber Institute for Brain Development. Study groups included 72 brain samples from individuals who died of acute opioid intoxication, 53 group-matched psychiatric control samples, and 28 group-matched normal control samples. Setting Maryland, USA. Participants Postmortem tissue samples of the dorsolateral prefrontal cortex from 153 deceased individuals (Mage = 35.42, SD = 9.43 years; 62% male; 77% White). Measurements Whole transcriptome RNA sequencing was used to generate exon counts, and differential expression was tested using limma-voom. Analyses controlled for relevant sociodemographic characteristics, technical covariates, and cryptic relatedness and batch effects using quality surrogate variable analysis. Gene set enrichment analyses (GSEA) also were conducted. Findings Sixteen genes were differentially expressed (i.e., FDR-corrected p < .10) in opioid samples compared to control samples. The top differentially expressed gene, NPAS4 (FDR adjusted p = .005), was downregulated in opioid samples and has previously been implicated in cocaine use. Enrichment analyses did not provide evidence for enrichment in pathways obviously related to opioid use. Conclusions NPAS4 is differentially expressed in the prefrontal cortex of subjects that died of an opioid overdose, providing evidence for another gene with functional relevance to opioid use and overdose.