Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder
Por:
Zillich E, Belschner H, Avetyan D, Andrade-Brito D, Martínez-Magaña JJ, Frank J, Mechawar N, Turecki G, Cabana-Domínguez J, Fernandez-Castillo N, Cormand B, Montalvo-Ortiz JL, Nöthen MM, Hansson AC, Rietschel M, Spanagel R, Witt SH and Zillich L
Publicada:
9 oct 2024
Ahead of Print:
9 oct 2024
Resumen:
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.
Filiaciones:
Zillich E:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Belschner H:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Avetyan D:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Andrade-Brito D:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
VA CT Healthcare Center, West Haven, CT, USA
Martínez-Magaña JJ:
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
VA CT Healthcare Center, West Haven, CT, USA
Frank J:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Mechawar N:
McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, QC, Canada
Department of Psychiatry, McGill University, Montreal, QC, Canada
Turecki G:
McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, QC, Canada
Department of Psychiatry, McGill University, Montreal, QC, Canada
Cabana-Domínguez J:
Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain
Fernandez-Castillo N:
Department de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain
Cormand B:
Department de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain
Montalvo-Ortiz JL:
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
VA CT Healthcare Center, West Haven, CT, USA
US Department of Veterans Affairs National Center of Posttraumatic Stress Disorder, Clinical Neurosciences Division, West Haven, CT, USA
Nöthen MM:
Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany
Hansson AC:
Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Rietschel M:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Spanagel R:
Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
German Center for Mental Health (DZPG), partner site Mannheim/Heidelberg/Ulm, Mannheim, Germany
Witt SH:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
German Center for Mental Health (DZPG), partner site Mannheim/Heidelberg/Ulm, Mannheim, Germany
Center for Innovative Psychiatric and Psychotherapeutic Research, Biobank, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Zillich L:
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
German Center for Mental Health (DZPG), partner site Mannheim/Heidelberg/Ulm, Mannheim, Germany
HITBR Hector Institute for Translational Brain Research gGmbH, Mannheim, Germany
gold
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