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Am J Psychiatry. 2015 Jun;172(6):543-52. doi: 10.1176/appi.ajp.2014.14030382. Epub 2015 May 18.

Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis.

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From the Institute of Psychiatry, King's College London; the MRC Social, Genetic, and Developmental Psychiatry Centre, London; the Department of Public Health, the Department of Mental Health and Substance Abuse Services, and the Institute for Molecular Medicine, University of Helsinki, Helsinki; the National Institute for Health and Welfare, Helsinki; the Central Institute of Mental Health, Medical Faculty Mannheim, the Department of Addictive Behaviour and Addiction Medicine, and the Department of Cognitive and Clinical Neuroscience, Heidelberg University, Mannheim, Germany; the Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland; Universitaetsklinikum Hamburg Eppendorf, Hamburg, Germany; the Department of Psychiatry, University of Montreal, and CHU Sainte-Justine Hospital, Montreal; NeuroSpin, Alternative Energies and Atomic Energy Commission (CEA), Paris; the Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Germany; the Departments of Psychiatry and Psychology, University of Vermont, Middlebury; the School of Physics and Astronomy and the School of Psychology, University of Nottingham, Nottingham, United Kingdom; Physikalisch-Technische Bundesanstalt, Braunschweig und Berlin, Germany; Institut National de la Santé et de la Recherche Médicale, INSERM CEA Unit 1000 "Imaging and Psychiatry," University Paris Sud, Orsay, and AP-HP Department of Adolescent Psychopathology and Medicine, Maison de Solenn, University Paris Descartes, Paris; Hospital for Sick Children and Rotman Research Institute, University of Toronto, Toronto; Montreal Neurological Institute, McGill University, Montreal; the Behavioural and Clinical Neuroscience Institute and the Department of Psychology, University of Cambridge, Cambridge, United Kingdom; the Department of Psychiatry and Psychotherapy and the Neuroimaging Center, Department of Psychology, Technische Universität Dresden, Germany; the Division of Biological Resea



The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior.


The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents.


Hypermethylation in the 3'-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task.


Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.

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