Epigenome-Wide Association Study and Multi-Tissue Replication of Individuals With Alcohol Use Disorder: Evidence for Abnormal Glucocorticoid Signaling Pathway Gene Regulation

Lohoff, Falk W.; Roy, Arunima; Jung, Jeesun; Longley, Martha; Rosoff, Daniel B.; Luo, Audrey; P'Connell, Emma; Sorcher, Jill L.; Sun, Hui; Schwandt, Melanie L.; Hodgkinson, Colin A.; Goldman, David; Momenan, Reza; McIntosh, Andrew M.; Adams, Mark; Walker, Rosie M.; Evans, Kathryn; Porteous, David J.; Smith, Alicia K.; Lee, Sang Hoon; Muench, Christine; Charlet, Katrin; Clarke, Toni; Kaminsky, Zachary

doi:10.1016/j.biopsych.2020.02.309

Cited by 8 publications

(18 citation statements)

References 65 publications

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“…We searched major studies of alcohol consumption for all of the genes replicated in three AUD studies 26,42,43 . Heterogenous Nuclear Ribonucleoprotein A1 ( HNRNPA1 ) was significantly hypomethylated in AUD cases in three studies that included saliva, lymphocytes and blood, 29,44,45 and HNRNPA1 methylation was inversely associated with alcohol consumption in blood 42,46 and saliva 26 . HNRNPA1 regulates RNA processing, including transcription, translation, splicing, stability and export.…”

Section: Recent Molecular Discoveriesmentioning

confidence: 99%

Epigenetics of alcohol use disorder—A review of recent advances in DNA methylation profiling

et al. 2021

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Alcohol use disorder (AUD) is a major contributor to morbidity and mortality worldwide. Although there is a heritable component, the etiology of AUD is complex and can involve environmental exposures like trauma and can be associated with many different patterns of alcohol consumption. Epigenetic modifications, which can mediate the influence of genetic variants and environmental variables on gene expression, have emerged as an important area of AUD research. Over the past decade, the number of studies investigating AUD and DNA methylation, a form of epigenetic modification, has grown rapidly. Yet we are still far from understanding how DNA methylation contributes to or reflects aspects of AUD. In this paper, we reviewed studies of DNA methylation and AUD and discussed how the field has evolved. We found that global DNA and candidate DNA methylation studies did not produce replicable results. To assess whether findings of epigenome‐wide association studies (EWAS) were replicated, we aggregated significant findings across studies and identified 184 genes and 15 gene ontological pathways that were differentially methylated in at least two studies and four genes and three gene ontological pathways that were differentially methylated in three studies. These genes and pathways repeatedly found enrichment of immune processes, which is in line with recent developments suggesting that the immune system may be altered in AUD. Finally, we assess the current limitations of studies of DNA methylation and AUD and make recommendations on how to design future studies to resolve outstanding questions.

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Section: Recent Molecular Discoveriesmentioning

confidence: 99%

Epigenetics of alcohol use disorder—A review of recent advances in DNA methylation profiling

et al. 2021

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“…Examining alterations in DNA-methylation in epigenome-wide association studies (EWAS) allows for the investigation of inter-individual differences which are attributable to a phenotype [8]. For example, a recent EWAS of AUD in peripheral blood suggests that networks in glucocorticoid signaling and inflammation-related genes are associated with AUD [9]. Human postmortem brain tissue is a sparse and valuable resource and allows a more direct characterization of AUD mechanisms than possible by analyzing peripheral blood [10].…”

Section: Introductionmentioning

confidence: 99%

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

Zillich

Frank

Streit

et al. 2021

Preprint

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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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“…While a few studies of AUD exist(2-8), they have not yet identified replicating sites across studies. This is likely due to small sample sizes, use of earlier arrays that captured a small number of sites, and inconsistent quality control, data analysis, and interpretation of significant findings (4). The one exception is a study conducted in whole blood that identified several sites associated with AUD across multiple cohorts (4).…”

Section: Introductionmentioning

confidence: 99%

“…This is likely due to small sample sizes, use of earlier arrays that captured a small number of sites, and inconsistent quality control, data analysis, and interpretation of significant findings (4). The one exception is a study conducted in whole blood that identified several sites associated with AUD across multiple cohorts (4). In contrast, studies of other alcohol outcomes including consumption and phosphatidylethanol, a metabolite of ethanol, have identified 7 sites that replicate across studies (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

“…DNAm studies are typically conducted using bulk tissue (e.g., whole blood or brain) that is composed of multiple cell-types, each with a potentially different DNAm profile. In studies using bulk tissue, including some previous alcohol studies (4,5,(9)(10)(11), estimates of cell-type proportions are included as covariates to protect against false positive associations (12). By focusing only on bulk tissue, however, potentially important associations may be missed.…”

Section: Introductionmentioning

confidence: 99%

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Dual methylation and hydroxymethylation study of alcohol use disorder

Clark

Chan

Zhao

et al. 2020

Preprint

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Background: Using a three-stage, multi-tissue design we sought to characterize methylation and hydroxymethylation changes in blood and brain associated with alcohol use disorder (AUD). Methods: In the discovery stage, we used epigenomic deconvolution to perform cell-type specific methylome-wide association studies within subpopulations of granulocytes/T-cells/B-cells/monocytes in 1,132 blood samples. Blood findings were examined for overlap with AUD-related methylation and hydroxymethylation in 50 human post-mortem brain samples in the brain overlap stage. Follow-up analyses investigated if overlapping findings mediated AUD-associated transcription changes in the same brain samples in the final stage. Results: Cell-type specific analyses in blood identified methylome-wide significant associations in monocytes and T-cells. One of the top genic findings is located in PLA2G4A, a gene required for monocyte chemotaxis. Alcohol inhibits monocyte chemotaxis, thereby contributing to alcohol-induced inflammation. The monocyte findings were significantly enriched for AUD-related methylation and hydroxymethylation in brain. Hydroxymethylation in BAIAP2 was found to mediate AUD-associated transcription in the same brain samples. BAIAP2 regulates dendritic spine density and is linked to cognitive deficits that are clinical features of advanced AUD. Conclusions: As part of the most comprehensive methylation study of AUD to date, this work involved the first cell-type specific methylation study of AUD conducted in blood, identifying methylation sites that are involved in alcohol-induced inflammation. In this first study to consider the role of hydroxymethylation in AUD, we found evidence for a novel mechanism for AUD brain-related impairments. Our results suggest promising new avenues for AUD research.

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Epigenome-Wide Association Study and Multi-Tissue Replication of Individuals With Alcohol Use Disorder: Evidence for Abnormal Glucocorticoid Signaling Pathway Gene Regulation

Cited by 8 publications

References 65 publications

Epigenetics of alcohol use disorder—A review of recent advances in DNA methylation profiling

Epigenetics of alcohol use disorder—A review of recent advances in DNA methylation profiling

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

Dual methylation and hydroxymethylation study of alcohol use disorder

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