DNA methylation of the glucocorticoid receptor gene predicts substance use in adolescence: longitudinal data from over 1000 young individuals

Raffetti, Elena; Melas, Philippe A.; Landgren, Anton; Andersson, Filip; Forsell, Yvonne; Lavebratt, Catharina; Galanti, Maria Rosaria

doi:10.1038/s41398-021-01601-6

Cited by 7 publications

(3 citation statements)

References 65 publications

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“…These data show that FKBP5 and SLC6A4 methylation levels are associated with brain connectivity and structure in regions relevant to adolescent depression. Raffetti et al [ 107 ] reported glucocorticoid receptor ( NR3C1 ) DNA methylation was significantly associated with a higher risk for substance use in adolescents, and NR3C1 exon 1F locus hypermethylation can predict substance use in adolescents. Roberson-Nay et al [ 108 ] investigated DNA methylation from 150 Caucasian monozygotic adolescent twins with or without major depression.…”

Section: Introductionmentioning

confidence: 99%

Dissecting early life stress-induced adolescent depression through epigenomic approach

Ochi

Dwivedi

2022

Mol Psychiatry

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Early life stress (ELS), such as abuse and neglect during childhood, can lead to psychiatric disorders in later life. Previous studies have suggested that ELS can cause profound changes in gene expression through epigenetic mechanisms, which can lead to psychiatric disorders in adulthood; however, studies on epigenetic modifications associated with ELS and psychiatric disorders in adolescents are limited. Moreover, how these epigenetic modifications can lead to psychiatric disorders in adolescents is not fully understood. Commonly, DNA methylation, histone modification, and the regulation of noncoding RNAs have been attributed to the reprogramming of epigenetic profiling associated with ELS. Although only a few studies have attempted to examine epigenetic modifications in adolescents with ELS, existing evidence suggests that there are commonalities and differences in epigenetic profiling between adolescents and adults. In addition, epigenetic modifications are sex-dependent and are influenced by the type of ELS. In this review, we have critically evaluated the current evidence on epigenetic modifications in adolescents with ELS, particularly DNA methylation and the expression of microRNAs in both preclinical models and humans. We have also clarified the impact of ELS on psychiatric disorders in adolescents to predict the development of neuropsychiatric disorders and to prevent and recover these disorders through personalized medicine.

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Section: Introductionmentioning

confidence: 99%

Dissecting early life stress-induced adolescent depression through epigenomic approach

Ochi

Dwivedi

2022

Mol Psychiatry

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“…Further, the expression of cocaine-induced locomotor sensitization was shown to be dependent on Ca v 1.2 signaling in mice ( 56 ). The NR3C1 gene encodes a glucocorticoid receptor for which downregulation in blood was observed in chronic cocaine users ( 57 ) and its DNAm levels were shown to predict substance use phenotypes in adolescents ( 58 ). Further, brain-specific conditional knock-out of NR3C1 flattened the dose-response curve for cocaine self-administration and reduced behavioral sensitization in an intravenous cocaine self-administration model in mice ( 59 ).…”

Section: Discussionmentioning

confidence: 99%

DNA methylation in cocaine use disorder–An epigenome-wide approach in the human prefrontal cortex

et al. 2023

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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.

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“…Further, the expression of cocaine-induced locomotor sensitization was shown to be dependent on Ca v 1.2 signaling in mice [55]. The NR3C1 gene encodes a glucocorticoid receptor for which downregulation in blood was observed in chronic cocaine users [56] and its DNAm levels were shown to predict substance use phenotypes in adolescents [57]. Further, brain-specific conditional knock-out of NR3C1 flattened the dose-response curve for cocaine self-administration and reduced behavioral sensitization in an intravenous cocaine self-administration model in mice [58].…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation in Cocaine Use Disorder – An Epigenome-wide Approach in the Human Prefrontal Cortex

Poisel

Zillich

Streit

et al. 2022

Preprint

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Cocaine use disorder (CUD) is characterized by a loss of control over drug intake and is associated with structural, functional, and molecular alterations in the brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes as 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. We investigated epigenome-wide DNA methylation signatures of CUD in human postmortem 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 and analyzed CUD-associated differentially methylated regions (DMRs). To assess the functional role of CUD-associated differential methylation, we performed Gene Ontology 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. While no 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 NPFFR2 and 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 networks derived from module hub genes revealed several addiction-related genes as highly connected nodes such as CACNA1C, NR3C1, and JUN. In BA9, we observed a trend toward epigenetic age acceleration in individuals with CUD remaining stable even after adjustment for covariates. Results from our study highlight that CUD is associated with epigenome-wide differences in DNA methylation 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. 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.

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DNA methylation of the glucocorticoid receptor gene predicts substance use in adolescence: longitudinal data from over 1000 young individuals

Cited by 7 publications

References 65 publications

Dissecting early life stress-induced adolescent depression through epigenomic approach

Dissecting early life stress-induced adolescent depression through epigenomic approach

DNA methylation in cocaine use disorder–An epigenome-wide approach in the human prefrontal cortex

DNA Methylation in Cocaine Use Disorder – An Epigenome-wide Approach in the Human Prefrontal Cortex

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