Brain Imaging‐Guided Analysis Reveals DNA Methylation Profiles Correlated with Insular Surface Area and Alcohol Use Disorder

Abstract Background Alcohol use disorder (AUD) is a chronic relapsing brain disorder. GABAA receptor (GABAAR) subunits are a target for the pharmacological effects of alcohol. Neurosteroids play an important role in the fine-tuning of GABAAR function in the brain. Recently, we have shown that AUD is associated with changes in DNA methylation mechanisms. However, the role of DNA methylation in the regulation of neurosteroid biosynthesis and GABAergic neurotransmission in AUD patients remains under-investigated. Methods In a cohort of postmortem brains from 20 male controls and AUD patients, we investigated the expression of GABAAR subunits and neurosteroid biosynthetic enzymes and their regulation by DNA methylation mechanisms. Neurosteroid levels were quantified by gas chromatography-mass spectrometry. Results The α 2 subunit expression was reduced due to increased DNA methylation at the gene promoter region in the cerebellum of AUD patients, a brain area particularly sensitive to the effects of alcohol. Alcohol-induced alteration in GABAAR subunits was also observed in the prefrontal cortex. Neurosteroid biosynthesis was also affected with reduced cerebellar expression of the 18kDa translocator protein and 3α-hydroxysteroid dehydrogenase mRNAs. Notably, increased DNA methylation levels were observed at the promoter region of 3α-hydroxysteroid dehydrogenase. These changes were associated with markedly reduced levels of allopregnanolone and pregnanolone in the cerebellum. Conclusion Given the key role of neurosteroids in modulating the strength of GABAAR-mediated inhibition, our data suggest that alcohol-induced impairments in GABAergic neurotransmission might be profoundly impacted by reduced neurosteroid biosynthesis most likely via DNA hypermethylation.

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Surface-Based Parameters of Brain Imaging in Male Patients with Alcohol Use Disorder

Psychiatry Investigation ◽

10.4306/pi.2016.13.5.511 ◽

2016 ◽

Vol 13 (5) ◽

pp. 511

Author(s):

Sungjin Im ◽

Sang-Gu Lee ◽

Jeonghwan Lee ◽

Siekyeong Kim ◽

Chul-Jin Shin ◽

...

Keyword(s):

Alcohol Use ◽

Brain Imaging ◽

Alcohol Use Disorder ◽

Male Patients

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W89. ALCOHOL USE DISORDER IS ASSOCIATED WITH DNA METHYLATION-BASED SHORTENING OF TELOMERE LENGTH AND REGULATED BY TESPA1: IMPLICATIONS FOR AGING

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2021.08.172 ◽

2021 ◽

Vol 51 ◽

pp. e191-e192

Author(s):

Jeesun Jung ◽

Josephin Wagner ◽

Falk Lohoff

Keyword(s):

Dna Methylation ◽

Alcohol Use ◽

Telomere Length ◽

Alcohol Use Disorder

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Epigenome-wide Association Study of Alcohol Use Disorder in Five Brain Regions

10.1101/2021.08.01.21261118 ◽

2021 ◽

Author(s):

Lea Zillich ◽

Josef Frank ◽

Fabian Streit ◽

Marion M Friske ◽

Jerome C Foo ◽

...

Keyword(s):

Dna Methylation ◽

Alcohol Use ◽

Brain Region ◽

Alcohol Use Disorder ◽

Brain Regions ◽

Anterior Cingulate ◽

Human Brain Tissue ◽

Postmortem Human Brain ◽

Association Analyses ◽

Cpg Sites

Alcohol Use Disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n=53) and controls (n=58) using a brain region-specific approach. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted Correlation Network Analysis (WGCNA), gene-set and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q < .05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < .05) were found in the CN (n=6), VS (n=18) and ACC (n=1). These findings were mapped to several genes including IREB2, SLC30A8, and DDAH2. In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD

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Multi-Omics Signatures of Alcohol Use Disorder in the Dorsal and Ventral Striatum

10.1101/2021.10.04.21264523 ◽

2021 ◽

Author(s):

Lea Zillich ◽

Eric Poisel ◽

Josef Frank ◽

Jerome C. Foo ◽

Marion M. Friske ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Alcohol Use ◽

Alcohol Use Disorder ◽

Molecular Mechanisms ◽

Ventral Striatum ◽

Cell Structure ◽

Dorsal Striatum ◽

Gene Set Enrichment Analysis ◽

Integrated Analysis

Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. In the dorsal striatum, we discovered differential expression (FDR<0.05) for a total of 50 genes. In the VS, DE genes at FDR<0.25 were overrepresented in a recent GWAS of problematic alcohol use. The ARHGEF15 gene was upregulated in all three brain regions. GSEA in CN and VS pointed towards cell-structure associated GO-terms and in PUT towards immune pathways. The WGCNA modules most strongly associated with AUD showed strong enrichment for immune response and inflammation pathways. Our integrated analysis of multi-omics data sets provides further evidence for the importance of immune-and inflammation-related processes in AUD.

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Genetics and Epigenetics of Aldehyde Dehydrogenase (ALDH2) in Alcohol Related Liver Disease

10.1101/2021.04.16.21255566 ◽

2021 ◽

Author(s):

Bhagyalakshmi Shankarappa ◽

Jayant Mahadevan ◽

Pratima Murthy ◽

Meera Purushottam ◽

Biju Viswanath ◽

...

Keyword(s):

Dna Methylation ◽

Liver Disease ◽

Alcohol Use ◽

Aldehyde Dehydrogenase ◽

Alcohol Use Disorder ◽

College Hospital ◽

Medical College ◽

Icd 10 ◽

Related Liver Disease ◽

Candidate Loci

Alcohol dependence and cirrhosis are key outcomes of excessive alcohol use. We studied the interaction between genetics and epigenetics at the aldehyde dehydrogenase (ALDH2) locus to understand differences in vulnerability to cirrhosis. Individuals were selected according to ICD 10 criteria for Alcohol use disorder with Cirrhosis (AUDC+ve, N=116) and Alcohol use disorder but without Cirrhosis (AUDC-ve, N=123) from the clinical services of Gastroenterology and Psychiatry at the St Johns Medical College Hospital(SJMCH). Fibroscan/sonographic evidence was used to rule out fibrosis for the AUDC-ve group. Genomic DNA from blood was used for genotyping at ALDH2 (rs2238151) locus. A subset of the samples was assessed for DNA methylation (AUDC+ve, N=50; AUDC-ve, N=50) at the LINE-1 and ALDH2 CpG loci by pyrosequencing on a PyroMark Q24. LINE1 DNA methylation did not differ between the groups. ALDH2 DNA methylation was significantly lower in AUDC+ve group compared to AUDC-ve group (P <0.001). Lower methylation in T-allele carriers compared to T-allele non-carriers of the ALDH2 locus (rs2238151) was observed in AUDC+ve subjects(P=0.009). Compromised methylation in blood DNA at candidate loci, in those with liver disease in the context of prolonged severe alcohol abuse, could be explored as a biomarker for current pathology, and further progression.

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Genetic association of FKBP5 with trait resilience in Korean male patients with alcohol use disorder

Scientific Reports ◽

10.1038/s41598-021-98032-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Chun Il Park ◽

Hae Won Kim ◽

Syung Shick Hwang ◽

Jee In Kang ◽

Se Joo Kim

Keyword(s):

Dna Methylation ◽

Alcohol Use ◽

Childhood Trauma ◽

Stress Responses ◽

Alcohol Use Disorder ◽

Risk Allele ◽

Linear Regression Analysis ◽

Allele Specific ◽

Male Patients ◽

Trait Resilience

AbstractThe FKBP5 gene is known to have an important role in alcohol use disorder (AUD) in response to stress and has been reported to affect stress responses by interacting with childhood trauma. This study investigated the effects of the FKBP5 polymorphism rs1360780 and childhood trauma on trait resilience in male patients with AUD. In addition, allele-specific associations between FKBP5 DNA methylation and resilience were examined. In total, 297 men with AUD were assessed for alcohol use severity, childhood trauma, resilience, and impulsivity. Genotyping for FKBP5 rs1360780 and DNA methylation were analyzed. The effects of the rs1360780 single nucleotide polymorphism (SNP) and clinical variables on resilience were tested using linear regression analysis. Possible associations between FKBP5 DNA methylation and resilience were tested with partial correlation analysis. The rs1360780 risk allele, a low education level, and high impulsivity were associated with diminished resilience, whereas no significant main or interaction effect of childhood trauma with the SNP rs1360780 genotype on resilience was shown. No significant association between FKBP5 DNA methylation and resilience was found. The present study demonstrated the involvement of the rs1360780 risk allele in trait resilience in men with AUD, suggesting that the genetic vulnerability of FKBP5 may influence resilience related to AUD.

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