Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation

Molecular Psychiatry, Journal Year: 2020, Volume and Issue: 26(6), P. 2224 - 2237

Published: May 12, 2020

Alcohol use disorder (AUD) is a chronic debilitating with limited treatment options and poorly defined pathophysiology. There are substantial genetic epigenetic components; however, the underlying mechanisms contributing to AUD remain largely unknown. We conducted largest DNA methylation epigenome-wide association study (EWAS) analyses currently available for (total N = 625) employed top hit replication (N 4798) using cross-tissue/cross-phenotypic approach goal of identifying novel targets relevant AUD. Results show that network differentially methylated regions in glucocorticoid signaling inflammation-related genes were associated alcohol behaviors. A probe consistently across all cohorts was located long non-coding RNA growth arrest specific five gene (GAS5) (p < 10-24). GAS5 has been implicated regulating transcriptional activity receptor multiple functions related apoptosis, immune function various cancers. Endophenotypic peripheral cortisol levels neuroimaging paradigms showed methylomic variation network-related probes stress phenotypes. Postmortem brain documented increased expression amygdala individuals Our data suggest differential system might influence inflammatory reactivity subsequently risk

Language: Английский

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Theoretical Frameworks and Mechanistic Aspects of Alcohol Addiction: Alcohol Addiction as a Reward Deficit/Stress Surfeit Disorder

Current topics in behavioral neurosciences, Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 1, 2023

Language: Английский

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Epigenome-wide association study of alcohol consumption in N = 8161 individuals and relevance to alcohol use disorder pathophysiology: identification of the cystine/glutamate transporter SLC7A11 as a top target

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 27(3), P. 1754 - 1764

Published: Dec. 2, 2021

Abstract Alcohol misuse is common in many societies worldwide and associated with extensive morbidity mortality, often leading to alcohol use disorders (AUD) alcohol-related end-organ damage. The underlying mechanisms contributing the development of AUD are largely unknown; however, growing evidence suggests that consumption strongly alterations DNA methylation. Identification alcohol-associated methylomic variation might provide novel insights into pathophysiology treatment targets for AUD. Here we performed largest single-cohort epigenome-wide association study (EWAS) date ( N = 8161) cross-validated findings populations relevant endophenotypes, as well animal models. Results showed 2504 CpGs significantly (Bonferroni p value < 6.8 × 10 −8 ) five probes located SLC7A11 7.75 −108 , JDP2 1.44 −56 GAS5 2.71 −47 TRA2B 3.54 −42 ), SLC43A1 1.18 −40 ). Genes annotated CpG sites implicated liver brain function, cellular response diseases, including hypertension Alzheimer’s disease. Two-sample Mendelian randomization confirmed causal relationship on risk (inverse variance weighted (IVW) 5.37 −09 A methylation-based predictor was able discriminate cases two independent cohorts 6.32 −38 5.41 −14 top EWAS probe cg06690548, cystine/glutamate transporter SLC7A11, replicated an cohort control participants 615) strong hypomethylation −17 Decreased methylation at this consistently clinical measures increased heavy drinking days −4 function enzymes (GGT 1.03 −21 ALT 1.29 −6 AST 1.97 )) individuals Postmortem analyses documented expression frontal cortex models marked liver, suggesting a mechanism by which leads hypomethylation-induced overexpression SLC7A11. Taken together, our discovery sample subsequent validation suggest role abnormal glutamate signaling mediated Our data intriguing given prominent important target therapeutic intervention.

Language: Английский

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Epigenome-wide association study of alcohol use disorder in five brain regions

Neuropsychopharmacology, Journal Year: 2021, Volume and Issue: 47(4), P. 832 - 839

Published: Nov. 13, 2021

Alcohol use disorder (AUD) is closely linked to the brain regions forming neurocircuitry of addiction. Postmortem human tissue enables direct study molecular pathomechanisms AUD. This aims identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n = 53) and controls 58) using a brain-region-specific approach, in which sample sizes ranged 46 94. Samples anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), putamen (PUT) were investigated. levels determined Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses carried out differentially methylated CpG-sites each region. Weighted correlation network analysis (WGCNA), gene-set, GWAS-enrichment performed. Two associated CN, 18 VS (q < 0.05). No epigenome-wide significant found BA9, ACC, or PUT. Differentially case-/control status 0.05) CN 6), 18), ACC 1). In VS, WGCNA-module showing strongest was enriched for immune-related pathways. first analyze methylation differences multiple consists largest date. Several novel implicated identified, providing basis explore epigenetic correlates

Language: Английский

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Stress‐Responsive Gene FK506‐Binding Protein 51 Mediates Alcohol‐Induced Liver Injury Through the Hippo Pathway and Chemokine (C‐X‐C Motif) Ligand 1 Signaling

Hepatology, Journal Year: 2021, Volume and Issue: 74(3), P. 1234 - 1250

Published: March 12, 2021

Chronic alcohol drinking is a major risk factor for alcohol-associated liver disease (ALD). FK506-binding protein 51 (FKBP5), cochaperone protein, involved in many key regulatory pathways. It known to be stress-related disorders, but there are no reports regarding its role ALD. This present study aimed examine the molecular mechanism of FKBP5 ALD.We found significant increase hepatic transcripts and expression patients with ALD mice fed chronic-plus-single binge ethanol. Loss Fkbp5 protected against alcohol-induced steatosis inflammation. Transcriptomic analysis revealed reduction Transcriptional enhancer TEF-1 (TEA) domain transcription 1 (Tead1) chemokine (C-X-C motif) ligand (Cxcl1) mRNA ethanol-fed Fkbp5-/- mice. Ethanol-induced was secondary down-regulation methylation level at 5' untranslated promoter region. The led induction TEAD1 through Hippo signaling pathway. can interact yes-associated (YAP) upstream kinase, mammalian Ste20-like kinase (MST1), affecting ability phosphorylate YAP inhibitory effect phosphorylation by ethanol leading nuclear translocation activation. Activation increased target, CXCL1, chemokine-mediated neutrophil recruitment, causing inflammation infiltration our mouse model.We identified an FKBP5-YAP-TEAD1-CXCL1 axis pathogenesis ameliorates injury pathway CXCL1 signaling, suggesting potential as target treatment

Language: Английский

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Targeting the Glucocorticoid Receptor Reduces Binge‐Like Drinking in High Drinking in the Dark (HDID‐1) Mice

Alcoholism Clinical and Experimental Research, Journal Year: 2020, Volume and Issue: 44(5), P. 1025 - 1036

Published: March 10, 2020

Background Chronic alcohol exposure can alter glucocorticoid receptor (GR) function in some brain areas that promotes escalated and compulsive‐like intake. GR antagonism prevent dependence‐induced escalation drinking, but very little is known about the role of regulating high‐risk nondependent Here, we investigate binge‐like drinking aversive responses to High Drinking Dark (HDID‐1) mice, which have been selectively bred for high blood ethanol (EtOH) concentrations (BECs) (DID) test, their founder line, HS/NPT. Methods In separate experiments, male female HDID‐1 mice were administered one several compounds inhibited or its negative regulator, FKBP51 (mifepristone [12.5, 25, 50, 100 mg/kg], CORT113176 [20, 40, 80 SAFit2 [10, 20, 40 mg/kg]) during a 2‐day DID task. EtOH consumption BECs measured. conditioned taste place aversion (CTA CPA, respectively) measured after mifepristone administration assess GR’s effects EtOH. Lastly, HS/NPT whether dissimilar from those would be observed, could suggest selective breeding had altered sensitivity on drinking. Results (with both CORT113176) reduced intake while inhibition did not BECs. contrast, no effect mice. Although exhibit attenuated CTA, enhance either CTA CPA Conclusion These data selection process increased support as genetic risk factor

Language: Английский

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Alcohol consumption, depression, overweight and cortisol levels as determining factors for NR3C1 gene methylation

Scientific Reports, Journal Year: 2021, Volume and Issue: 11(1)

Published: March 24, 2021

Abstract The NR3C1 glucocorticoid receptor (GR) gene is a component of the stress response system, which can be regulated by epigenetic mechanisms. methylation has been associated with trauma and mental issues, including depression, post-traumatic stress, anxiety, personality disorders. Previous studies have reported that stressful events are involved in methylation, suggesting its regulation under environmental effects complex. present study aimed to analyze associations involving stressors such as socioeconomic status, health conditions, lifestyle relation adults. This included 386 individual users Brazilian Public Unified Health System (SUS), evaluated body mass index, cortisol levels, lifestyle. Data were correlated determined using DNA pyrosequencing. results showed alcohol consumption, overweight, high levels related demethylation, while depression was methylation. Habits, lifestyle, status may influence via revealing complexity impacts on

Language: Английский

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Association between childhood maltreatment, psychopathology and DNA methylation of genes involved in stress regulation: Evidence from a study in Borderline Personality Disorder

PLoS ONE, Journal Year: 2021, Volume and Issue: 16(3), P. e0248514 - e0248514

Published: March 11, 2021

Previous research suggests that childhood maltreatment is associated with epigenetic modification of genes involved in hypothalamic-pituitary-adrenal (HPA) functioning, which could cause dysregulation the stress response system. If pervasive, this may be development stress-related disorder adults, including affective disorders, anxiety post-traumatic (PTSD) or borderline-personality (BPD). The majority studies have focused on DNA methylation glucocorticoid receptor gene (NR3C1) and FKBP5 encoding gene, regulates sensitivity (GR). How NR3C1 interferes adversity psychopathology as well empathy an under-researched issue. Here, we sought to investigate association a sample 89 individuals (44 healthy participants 45 patients diagnosed BPD) 1 F promoter region intron 7 different measures empathy. Methylation (bin 2) correlated (SCL-90-R) global psychopathological symptom load index (GSI), lower empathic perspective-taking abilities. Psychopathology impairments level maltreatment. No difference was observed between clinical non-clinical group. BPD compared controls, yet small differences. results are discussed regarding their biological relevance, possible evolutionary explanations. In short, regulation GR by scores, while no correlation emerged severity adversity.

Language: Английский

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Glucocorticoid receptor modulators decrease alcohol self-administration in male rats

Neuropharmacology, Journal Year: 2021, Volume and Issue: 188, P. 108510 - 108510

Published: Feb. 26, 2021

Language: Английский

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Epigenetic Insights into Substance Use Disorder and Associated Psychiatric Conditions

Complex Psychiatry, Journal Year: 2025, Volume and Issue: 11(1), P. 12 - 36

Published: March 3, 2025

Background: Substance use disorder (SUD) is closely associated with epigenetic modifications that significantly impact mental health outcomes. Alcohol and drug misuse induce widespread changes in the epigenome transcriptome of central nervous system, disrupting critical processes such as reward signaling emotional regulation. These alterations regulation gene expression often persist even after substance cessation, potentially contributing to onset or worsening psychiatric conditions, including schizophrenia, depression, stress, anxiety. Summary: This review delves into key mechanisms underlying SUD its comorbid disorders, a focus on DNA methylation, histone modifications, noncoding RNA Additionally, it examines influence environmental biological factors evaluates emerging epigenetic-based therapeutic strategies aimed at treating related conditions. Key Messages: Gaining deeper understanding driving disorders crucial for development effective interventions. highlights potential pharmacological mitigate societal personal burdens linked complications.

Language: Английский

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