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      Molecular Psychiatry
      Nature Publishing Group

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          Abstract

          The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts ( n total=13 317; 54% women; mean age across cohorts 42–76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry ( n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90–0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10 −7. Analysis of the monocyte-derived DNA ( n=1251) identified 62 alcohol-related CpGs at P<1 × 10 -7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

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          Transcriptional and epigenetic mechanisms of addiction.

          Investigations of long-term changes in brain structure and function that accompany chronic exposure to drugs of abuse suggest that alterations in gene regulation contribute substantially to the addictive phenotype. Here, we review multiple mechanisms by which drugs alter the transcriptional potential of genes. These mechanisms range from the mobilization or repression of the transcriptional machinery - including the transcription factors ΔFOSB, cyclic AMP-responsive element binding protein (CREB) and nuclear factor-κB (NF-κB) - to epigenetics - including alterations in the accessibility of genes within their native chromatin structure induced by histone tail modifications and DNA methylation, and the regulation of gene expression by non-coding RNAs. Increasing evidence implicates these various mechanisms of gene regulation in the lasting changes that drugs of abuse induce in the brain, and offers novel inroads for addiction therapy.
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            Analysing and interpreting DNA methylation data.

            DNA methylation is an epigenetic mark that has suspected regulatory roles in a broad range of biological processes and diseases. The technology is now available for studying DNA methylation genome-wide, at a high resolution and in a large number of samples. This Review discusses relevant concepts, computational methods and software tools for analysing and interpreting DNA methylation data. It focuses not only on the bioinformatic challenges of large epigenome-mapping projects and epigenome-wide association studies but also highlights software tools that make genome-wide DNA methylation mapping more accessible for laboratories with limited bioinformatics experience.
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              Overview: How Is Alcohol Metabolized by the Body?

              Alcohol is eliminated from the body by various metabolic mechanisms. The primary enzymes involved are aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH), cytochrome P450 (CYP2E1), and catalase. Variations in the genes for these enzymes have been found to influence alcohol consumption, alcohol-related tissue damage, and alcohol dependence. The consequences of alcohol metabolism include oxygen deficits (i.e., hypoxia) in the liver; interaction between alcohol metabolism byproducts and other cell components, resulting in the formation of harmful compounds (i.e., adducts); formation of highly reactive oxygen-containing molecules (i.e., reactive oxygen species [ROS]) that can damage other cell components; changes in the ratio of NADH to NAD+ (i.e., the cell’s redox state); tissue damage; fetal damage; impairment of other metabolic processes; cancer; and medication interactions. Several issues related to alcohol metabolism require further research.
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                Author and article information

                Journal
                Mol Psychiatry
                Mol. Psychiatry
                Molecular Psychiatry
                Nature Publishing Group
                1359-4184
                1476-5578
                February 2018
                15 November 2016
                : 23
                : 2
                : 422-433
                Affiliations
                [1 ]The Framingham Heart Study , Framingham, MA, USA
                [2 ]The Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute , Bethesda, MD, USA
                [3 ]Department of Biostatistics, Boston University School of Public Health , Boston, MA, USA
                [4 ]Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh , Edinburgh, UK
                [5 ]Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh , Edinburgh, UK
                [6 ]Queensland Brain Institute, The University of Queensland , Brisbane, QLD, Australia
                [7 ]Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University , Uppsala, Sweden
                [8 ]Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health , Neuherberg, Germany
                [9 ]Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health , Neuherberg, Germany
                [10 ]Department of Twin Research and Genetic Epidemiology, King’s College London , London, UK
                [11 ]Division of Public Health Sciences, Wake Forest School of Medicine , Winston-Salem, NC, USA
                [12 ]Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [13 ]Department of Genetics, University of North Carolina , Chapel Hill, NC, USA
                [14 ]Department of Internal Medicine, Erasmus MC , Rotterdam, The Netherlands
                [15 ]Translational Gerontology Branch, National Institute on Aging , Baltimore, MD, USA
                [16 ]MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge , Cambridge, UK
                [17 ]Department of Epidemiology, University of Alabama at Birmingham , Birmingham, AL, USA
                [18 ]Cardiovascular Health Research Unit, Department of Medicine, University of Washington , Seattle, WA, USA
                [19 ]German Center for Diabetes Research (DZD) , München-Neuherberg, Germany
                [20 ]Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University , Düsseldorf, Germany
                [21 ]Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine , Atlanta, GA, USA
                [22 ]School of Biomedical Informatics and School of Public Health, The University of Texas Health Science Center at Houston , Houston, TX, USA
                [23 ]Department of Epidemiology, University of North Carolina at Chapel Hill , Chapel Hill, NC, USA
                [24 ]Hebrew SeniorLife, Harvard Medical School , Boston, MA, USA
                [25 ]Harvard School of Public Health, Harvard University , Boston, MA, USA
                [26 ]Division of Biostatistics, School of Public Health, University of Minnesota , Minneapolis, MN, USA
                [27 ]Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD, Australia
                [28 ]Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health , Neuherberg, Germany
                [29 ]Institute of Human Genetics, Technische Universität München , München, Germany
                [30 ]Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität , Munich, Germany
                [31 ]Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health , Neuherberg, Germany
                [32 ]DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance , Munich, Germany
                [33 ]Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center , Torrance, CA, USA
                [34 ]Max-Planck Institute of Psychiatry , Munich, Germany
                [35 ]Division of Depression and Anxiety Disorders, McLean Hospital , Belmont, MA, USA
                [36 ]HudsonAlpha Institute for Biotechnology , Huntsville, AL, USA
                [37 ]Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health , Bethesda, MD, USA
                [38 ]Geriatric Unit, Azienda Sanitaria Firenze (ASF) , Florence, Italy
                [39 ]Department of Internal Medicine, Wake Forest School of Medicine , Winston-Salem, NC, USA
                [40 ]Department of Environmental Health, Harvard T.H. Chan School of Public Health , Boston, MA, USA
                [41 ]Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala University , Uppsala, Sweden
                [42 ]Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University , Uppsala, Sweden
                [43 ]Department of Epidemiology, Erasmus MC , Rotterdam, The Netherlands
                [44 ]Departments of Environmental Health and Epidemiology, Harvard T.H. Chan School of Public Health , Boston, MA, USA
                [45 ]VA Boston Healthcare System and Boston University Schools of Public Health and Medicine , Jamaica Plain, MA, USA
                [46 ]Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University , Uppsala, Sweden
                [47 ]Department of Genetics, Department of Biostatistics and Department of Computer Science, University of North Carolina , Chapel Hill, NC, USA
                [48 ]Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston , Houston TX, USA
                [49 ]College of Public Health, University of Kentucky , Lexington, KY, USA
                [50 ]Department of Human Genetics, Emory University School of Medicine , Atlanta, GA, USA
                [51 ]Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University , New York, NY, USA
                [52 ]Department of Psychology, University of Edinburgh , Edinburgh, UK
                [53 ]Department of Health and Human Services, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, NC, USA
                [54 ]Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine , Stanford, CA, USA
                Author notes
                [* ]The Population Sciences Branch, Division of Intramural Research, The Framingham Heart Study, National Heart, Lung and Blood Institute , Perini Building, Framingham, MA 01701, USA. E-mail: chunyu.liu@ 123456nih.gov or levyd@ 123456nhlbi.nih.gov
                [55]

                These authors contributed equally to this work.

                [56]

                These authors jointly supervised the work.

                Article
                mp2016192
                10.1038/mp.2016.192
                5575985
                27843151
                fdd3efbf-05e4-443a-8f58-f834bd452c5b
                Copyright © 2018 The Author(s)

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                : 11 February 2016
                : 05 September 2016
                : 14 September 2016
                Categories
                Original Article

                Molecular medicine
                Molecular medicine

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