Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid dependence

Abstract

Opioid dependence is a highly heterogeneous disease driven by a variety of genetic and environmental risk factors which have yet to be fully elucidated. We interrogated the effects of opioid dependence on the brain using ChIP-seq to quantify patterns of H3K27 acetylation in dorsolateral prefrontal cortical neurons isolated from 51 opioid-overdose cases and 51 accidental death controls. Among opioid cases, we observed global hypoacetylation and identified 388 putative enhancers consistently depleted for H3K27ac. Machine learning on H3K27ac patterns predicts case-control status with high accuracy. We focus on case-specific regulatory alterations, revealing 81,399 hypoacetylation events, uncovering vast inter-patient heterogeneity. We developed a strategy to decode this heterogeneity based on convergence analysis, which leveraged promoter-capture Hi-C to identify five genes over-burdened by alterations in their regulatory network or "plexus": ASTN2, KCNMA1, DUSP4, GABBR2, ENOX1. These convergent loci are enriched for opioid use disorder risk genes and heritability for generalized anxiety, number of sexual partners, and years of education. Overall, our multi-pronged approach uncovers neurobiological aspects of opioid dependence and captures genetic and environmental factors perpetuating the opioid epidemic.

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

“…Gene expression studies of postmortem human brains represent an opportunity to get closer to the disease state and elucidate the etiology of OUD and comorbid conditions in ways not possible using genetics alone. There is strong evidence for acute and persistent changes in central nervous system gene expression resulting from exposure to substances of abuse 24,25 , stress 26 , and their associated disorders including OUD 27 , alcohol use disorder (AUD) 28,29 , and post-traumatic stress disorder (PTSD) 30,31 .…”