Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder

Abstract

DNA methylation; Gene expression; Cocaine use disorder

Metilación del ADN; Expresión génica; Trastorno por consumo de cocaína

Metilació de l'ADN; Expressió gènica; Trastorn per consum de cocaïna

Structural and functional changes of the brain are assumed to contribute to excessive cocaine intake, craving, and relapse in cocaine use disorder (CUD). Epigenetic and transcriptional changes were hypothesized as a molecular basis for CUD-associated brain alterations. Here we performed a multi-omics study of CUD by integrating epigenome-wide methylomic (N = 42) and transcriptomic (N = 25) data from the same individuals using postmortem brain tissue of Brodmann Area 9 (BA9). Of the N = 1 057 differentially expressed genes (p < 0.05), one gene, ZFAND2A, was significantly upregulated in CUD at transcriptome-wide significance (q < 0.05). Differential alternative splicing (AS) analysis revealed N = 98 alternatively spliced transcripts enriched in axon and dendrite extension pathways. Strong convergent overlap in CUD-associated expression deregulation was found between our BA9 cohort and independent replication datasets. Epigenomic, transcriptomic, and AS changes in BA9 converged at two genes, ZBTB4 and INPP5E. In pathway analyses, synaptic signaling, neuron morphogenesis, and fatty acid metabolism emerged as the most prominently deregulated biological processes. Drug repositioning analysis revealed glucocorticoid receptor targeting drugs as most potent in reversing the CUD expression profile. Our study highlights the value of multi-omics approaches for an in-depth molecular characterization and provides insights into the relationship between CUD-associated epigenomic and transcriptomic signatures in the human prefrontal cortex.

Funding supporting this study was provided by the German Federal Ministry of Education and Research (BMBF) within the e:Med research program SysMedSUDs: “A systems-medicine approach toward distinct and shared resilience and pathological mechanisms of substance use disorders” (01ZX01909 to RS, MR, ACH, and SHW). In addition, by the Deutsche Forschungsgemeinschaft (DFG) through the collaborative research centre TRR265: “Losing and Regaining Control over Drug Intake” [83] (Project ID 402170461 to SHW, RS, ACH and MR), the Hetzler Foundation for Addiction Research (to ACH), the ERA-NET program: Psi-Alc (01EZ1908), Spanish ‘Ministerio de Ciencia, Innovación y Universidades’ (PID2021-1277760B-I100, to BC), ‘Generalitat de Catalunya/AGAUR’ (2021-SGR-01093, to BC), ICREA Academia 2021, ‘Fundació La Marató de TV3′ (202218-31, to BC) and from ‘Ministerio de Sanidad, Servicios Sociales e Igualdad/Plan Nacional Sobre Drogas’ (PNSD-2020I042, to NF-C). The project has been carried out using the Mannheim (CIMH) infrastructure of the German Center for Mental Health (DZPG). Open Access funding enabled and organized by Projekt DEAL.