Structural and functional changes in the brain are thought to contribute to excessive cocaine use, craving, and relapse in cocaine use disorder (CUD). Epigenetic and transcriptional changes have been hypothesized as a molecular basis for CUD-associated brain alterations. This multi-omics study integrated epigenome-wide methylomic (N = 42) and transcriptomic (N=25) data from postmortem brain tissue of Brodmann Area 9 (BA9) from the same individuals. One gene, ZFAND2A, was significantly upregulated in CUD at transcriptome-wide significance (q <0.05). Differential alternative splicing (AS) analysis revealed 98 alternatively spliced transcripts enriched in axon and dendrite extension pathways. Strong overlap in CUD-associated expression deregulation was found between the BA9 cohort and independent replication datasets. Epigenomic, transcriptomic, and AS changes converged at two genes, ZBTB4 and INPP5E. Pathway analyses revealed synaptic signaling, neuron morphogenesis, and fatty acid metabolism as prominently deregulated processes. Drug repositioning analysis identified glucocorticoid receptor targeting drugs as potentially effective in reversing the CUD expression profile.

Eric Zillich, Hanna Belschner, Diana Avetyan, Diego Andrade-Brito, José Jaime Martínez-Magaña, Josef Frank, Naguib Mechawar, Gustavo Turecki, Judit Cabana-Domínguez, Noèlia Fernàndez-Castillo, Bru Cormand, Janitza L. Montalvo-Ortiz, Markus M. Nöthen, Anita C. Hansson, Marcella Rietschel, Rainer Spanagel, Stephanie H. Witt, Lea Zillich