title: A DNA methylation biomarker of alcohol consumption.
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 (ntotal=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.
authors.affiliation: The Framingham Heart Study, Framingham, MA, USA.|The Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: R E
authors.initials: RE
authors.lastname: Marioni
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Å K
authors.initials: ÅK
authors.lastname: Hedman
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Pfeiffer
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: P-C
authors.initials: PC
authors.lastname: Tsai
authors.affiliation: Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Reynolds
authors.affiliation: Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Just
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Duan
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: C G
authors.initials: CG
authors.lastname: Boer
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: C E
authors.initials: CE
authors.lastname: Elks
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Aslibekyan
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Brody
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Kühnel
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Herder
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Almli
authors.affiliation: School of Biomedical Informatics and School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhi
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Framingham Heart Study, Framingham, MA, USA.|The Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA.
authors.forename: T
authors.initials: T
authors.lastname: Huan
authors.affiliation: The Framingham Heart Study, Framingham, MA, USA.|The Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Yao
authors.affiliation: The Framingham Heart Study, Framingham, MA, USA.|The Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Mendelson
authors.affiliation: The Framingham Heart Study, Framingham, MA, USA.|The Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA.|Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Joehanes
authors.affiliation: Harvard School of Public Health, Harvard University, Boston, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: S-A
authors.initials: SA
authors.lastname: Love
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
authors.forename: W
authors.initials: W
authors.lastname: Guan
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.|Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Shah
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.|Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: A F
authors.initials: AF
authors.lastname: McRae
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kretschmer
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, München, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.|Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Peters
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.|Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: P M
authors.initials: PM
authors.lastname: Visscher
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.|Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: N R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Wiggins
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Smith
authors.affiliation: Max-Planck Institute of Psychiatry, Munich, Germany.
authors.forename: E B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Division of Depression and Anxiety Disorders, McLean Hospital, Belmont, MA, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Ressler
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Irvin
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Absher
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hernandez
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bandinelli
authors.affiliation: Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lohman
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Trevisi
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Gustafsson
authors.affiliation: Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: J H
authors.initials: JH
authors.lastname: Sandling
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Stolk
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: A G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: I
authors.initials: I
authors.lastname: Yet
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: J E
authors.initials: JE
authors.lastname: Castillo-Fernandez
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: T D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Departments of Environmental Health and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Schwartz
authors.affiliation: VA Boston Healthcare System and Boston University Schools of Public Health and Medicine, Jamaica Plain, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Vokonas
authors.affiliation: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Lind
authors.affiliation: Department of Genetics, Department of Biostatistics and Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Fornage
authors.affiliation: College of Public Health, University of Kentucky, Lexington, KY, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Arnett
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sotoodehnia
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: K K
authors.initials: KK
authors.lastname: Ong
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: J B J
authors.initials: JBJ
authors.lastname: van Meurs
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: K N
authors.initials: KN
authors.lastname: Conneely
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Baccarelli
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: I J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: J T
authors.initials: JT
authors.lastname: Bell
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: North
authors.affiliation: Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: 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.
authors.forename: S J
authors.initials: SJ
authors.lastname: London
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: The Framingham Heart Study, Framingham, MA, USA.|The Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Levy
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000235:genetics* / Q000378:metabolism; D019973:Alcohol-Related Disorders / Q000235:genetics* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D044383:Black People / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D044127:Epigenesis, Genetic; D000431:Ethanol / Q000097:blood / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D044465:White People / Q000235:genetics
chemical_list: D015415:Biomarkers; D000431:Ethanol