DNA methylation in cocaine use disorder–An epigenome-wide approach in the human prefrontal cortex
BackgroundCocaine use disorder (CUD) is characterized by a loss of control over cocaine intake and is associated with structural, functional, and molecular alterations in the human brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and...
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Psychiatry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1075250/full |
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| author | Eric Poisel Lea Zillich Fabian Streit Josef Frank Marion M. Friske Jerome C. Foo Naguib Mechawar Naguib Mechawar Gustavo Turecki Gustavo Turecki Anita C. Hansson Markus M. Nöthen Marcella Rietschel Rainer Spanagel Stephanie H. Witt Stephanie H. Witt |
| author_facet | Eric Poisel Lea Zillich Fabian Streit Josef Frank Marion M. Friske Jerome C. Foo Naguib Mechawar Naguib Mechawar Gustavo Turecki Gustavo Turecki Anita C. Hansson Markus M. Nöthen Marcella Rietschel Rainer Spanagel Stephanie H. Witt Stephanie H. Witt |
| author_sort | Eric Poisel |
| collection | DOAJ |
| description | BackgroundCocaine use disorder (CUD) is characterized by a loss of control over cocaine intake and is associated with structural, functional, and molecular alterations in the human brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes observed in CUD. Most evidence of cocaine-associated epigenetic changes comes from animal studies while only a few studies have been performed using human tissue.MethodsWe investigated epigenome-wide DNA methylation (DNAm) signatures of CUD in human post-mortem brain tissue of Brodmann area 9 (BA9). A total of N = 42 BA9 brain samples were obtained from N = 21 individuals with CUD and N = 21 individuals without a CUD diagnosis. We performed an epigenome-wide association study (EWAS) and analyzed CUD-associated differentially methylated regions (DMRs). To assess the functional role of CUD-associated differential methylation, we performed Gene Ontology (GO) enrichment analyses and characterized co-methylation networks using a weighted correlation network analysis. We further investigated epigenetic age in CUD using epigenetic clocks for the assessment of biological age.ResultsWhile no cytosine-phosphate-guanine (CpG) site was associated with CUD at epigenome-wide significance in BA9, we detected a total of 20 CUD-associated DMRs. After annotation of DMRs to genes, we identified Neuropeptide FF Receptor 2 (NPFFR2) and Kalirin RhoGEF Kinase (KALRN) for which a previous role in the behavioral response to cocaine in rodents is known. Three of the four identified CUD-associated co-methylation modules were functionally related to neurotransmission and neuroplasticity. Protein-protein interaction (PPI) networks derived from module hub genes revealed several addiction-related genes as highly connected nodes such as Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit (JUN). In BA9, we observed a trend toward epigenetic age acceleration (EAA) in individuals with CUD remaining stable even after adjustment for covariates.ConclusionResults from our study highlight that CUD is associated with epigenome-wide differences in DNAm levels in BA9 particularly related to synaptic signaling and neuroplasticity. This supports findings from previous studies that report on the strong impact of cocaine on neurocircuits in the human prefrontal cortex (PFC). Further studies are needed to follow up on the role of epigenetic alterations in CUD focusing on the integration of epigenetic signatures with transcriptomic and proteomic data. |
| first_indexed | 2024-04-10T15:19:16Z |
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| series | Frontiers in Psychiatry |
| spelling | doaj.art-4e436d3f2e924495b3a751f3acaab3682023-02-14T15:33:21ZengFrontiers Media S.A.Frontiers in Psychiatry1664-06402023-02-011410.3389/fpsyt.2023.10752501075250DNA methylation in cocaine use disorder–An epigenome-wide approach in the human prefrontal cortexEric Poisel0Lea Zillich1Fabian Streit2Josef Frank3Marion M. Friske4Jerome C. Foo5Naguib Mechawar6Naguib Mechawar7Gustavo Turecki8Gustavo Turecki9Anita C. Hansson10Markus M. Nöthen11Marcella Rietschel12Rainer Spanagel13Stephanie H. Witt14Stephanie H. Witt15Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyInstitute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyMcGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, QC, CanadaDepartment of Psychiatry, McGill University, Montreal, QC, CanadaMcGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, QC, CanadaDepartment of Psychiatry, McGill University, Montreal, QC, CanadaInstitute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyInstitute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, GermanyDepartment of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyInstitute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyDepartment of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyCenter for Innovative Psychiatric and Psychotherapeutic Research, Biobank, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyBackgroundCocaine use disorder (CUD) is characterized by a loss of control over cocaine intake and is associated with structural, functional, and molecular alterations in the human brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes observed in CUD. Most evidence of cocaine-associated epigenetic changes comes from animal studies while only a few studies have been performed using human tissue.MethodsWe investigated epigenome-wide DNA methylation (DNAm) signatures of CUD in human post-mortem brain tissue of Brodmann area 9 (BA9). A total of N = 42 BA9 brain samples were obtained from N = 21 individuals with CUD and N = 21 individuals without a CUD diagnosis. We performed an epigenome-wide association study (EWAS) and analyzed CUD-associated differentially methylated regions (DMRs). To assess the functional role of CUD-associated differential methylation, we performed Gene Ontology (GO) enrichment analyses and characterized co-methylation networks using a weighted correlation network analysis. We further investigated epigenetic age in CUD using epigenetic clocks for the assessment of biological age.ResultsWhile no cytosine-phosphate-guanine (CpG) site was associated with CUD at epigenome-wide significance in BA9, we detected a total of 20 CUD-associated DMRs. After annotation of DMRs to genes, we identified Neuropeptide FF Receptor 2 (NPFFR2) and Kalirin RhoGEF Kinase (KALRN) for which a previous role in the behavioral response to cocaine in rodents is known. Three of the four identified CUD-associated co-methylation modules were functionally related to neurotransmission and neuroplasticity. Protein-protein interaction (PPI) networks derived from module hub genes revealed several addiction-related genes as highly connected nodes such as Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit (JUN). In BA9, we observed a trend toward epigenetic age acceleration (EAA) in individuals with CUD remaining stable even after adjustment for covariates.ConclusionResults from our study highlight that CUD is associated with epigenome-wide differences in DNAm levels in BA9 particularly related to synaptic signaling and neuroplasticity. This supports findings from previous studies that report on the strong impact of cocaine on neurocircuits in the human prefrontal cortex (PFC). Further studies are needed to follow up on the role of epigenetic alterations in CUD focusing on the integration of epigenetic signatures with transcriptomic and proteomic data.https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1075250/fullcocaineDNA methylationaddictionepigeneticsEWASprefrontal cortex |
| spellingShingle | Eric Poisel Lea Zillich Fabian Streit Josef Frank Marion M. Friske Jerome C. Foo Naguib Mechawar Naguib Mechawar Gustavo Turecki Gustavo Turecki Anita C. Hansson Markus M. Nöthen Marcella Rietschel Rainer Spanagel Stephanie H. Witt Stephanie H. Witt DNA methylation in cocaine use disorder–An epigenome-wide approach in the human prefrontal cortex Frontiers in Psychiatry cocaine DNA methylation addiction epigenetics EWAS prefrontal cortex |
| title | DNA methylation in cocaine use disorder–An epigenome-wide approach in the human prefrontal cortex |
| title_full | DNA methylation in cocaine use disorder–An epigenome-wide approach in the human prefrontal cortex |
| title_fullStr | DNA methylation in cocaine use disorder–An epigenome-wide approach in the human prefrontal cortex |
| title_full_unstemmed | DNA methylation in cocaine use disorder–An epigenome-wide approach in the human prefrontal cortex |
| title_short | DNA methylation in cocaine use disorder–An epigenome-wide approach in the human prefrontal cortex |
| title_sort | dna methylation in cocaine use disorder an epigenome wide approach in the human prefrontal cortex |
| topic | cocaine DNA methylation addiction epigenetics EWAS prefrontal cortex |
| url | https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1075250/full |
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