Heterogeneous epigenetic variation converges on splicing dysregulation in opioid addiction

Here, we leverage individual heterogeneity to identify epigenetic variation linked to opioid overdose by profiling H3K27ac ChIP-seq in nucleus accumbens (NAc) from 91 overdose cases and accidental death controls. Machine learning models built on combinations of peaks distinguished cases from controls with high accuracy (AUROC = 0.95) and were enriched for OUD genetic risk.

We defined individual-specific H3K27ac changes as Variant Enhancer Loci (VEL) and observed four-fold greater convergence on shared target genes in NAc than in prefrontal cortex. Convergent VEL target genes were enriched in independent OUD cohorts, and RNA splicing emerged as the top-enriched ontology. Knockdown of the splicing regulator CELF5 in iPSC-derived medium spiny neurons disrupted extracellular matrix organization genes.