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Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders

Nature Mental Health volume 1, pages 210–223 (2023)Cite this article

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Abstract

Genetic liability to substance use disorders can be parsed into loci that confer general or substance-specific addiction risk. We report a multivariate genome-wide association meta-analysis that disaggregates general and substance-specific loci from published summary statistics of problematic alcohol use, problematic tobacco use, cannabis use disorder and opioid use disorder in a sample of 1,025,550 individuals of European descent and 92,630 individuals of African descent. Nineteen independent single-nucleotide polymorphisms were genome-wide significant (P < 5 × 10–8) for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries, PDE4B was significant (among other genes), suggesting dopamine regulation as a cross-substance vulnerability. An addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis and 1 for opioids) included metabolic and receptor genes. These findings provide insight into genetic risk loci for substance use disorders that could be leveraged as treatment targets.

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Fig. 1: Manhattan plot of the addiction-rf GWAS results.
Fig. 2: Manhattan plot of the transcriptome-wide association study results for addiction-rf.
Fig. 3: PheWAS of genetic correlations using MASSIVE.
Fig. 4: Polygenic risk score prediction in Yale–Penn 3.

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Data availability

The MVP summary statistics were obtained via an approved dbGaP application (phs001672.v4.p1). For details on the MVP, see https://www.research.va.gov/mvp/ and ref. 76. This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration, and was supported by the Veterans Administration Cooperative Studies Program award G002.

Publicly available data were also downloaded from the psychiatric genomics consortium (https://www.med.unc.edu/pgc/) and the GSCAN consortium (https://conservancy.umn.edu/handle/11299/201564).

The datasets used for the BioVU analyses described were obtained from Vanderbilt University Medical Center’s biorepository, which is supported by numerous sources: institutional funding, private agencies and federal grants. These include the National Institutes of Health-funded Shared Instrumentation grant S10RR025141; and Clinical and Translational Science Awards (CTSA) grants UL1TR002243, UL1TR000445 and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962 and R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/.

Data from Yale–Penn 1 are available through dbGAP accession no phs000425.v1.p1 including 1,889 African American subjects and 1,020 European-American subjects. Yale–Penn 1 data are also available through dbGAP accession no phs000952.v1.p1 including 1,531 African American subjects and 1,339 self-reported European-American subjects. Summary statistics for all Yale–Penn data are available on request to J.G. (joel.gelernter@yale.edu).

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Acknowledgements

The authors would like to thank Cold Harbor Labroatory for posting a preprint of this work on MedRxiv (https://www.medrxiv.org/). The authors thank Million Veteran Program (MVP) staff, researchers and volunteers, who have contributed to MVP, and especially participants who previously served their country in the military and now generously agreed to enroll in the study. Funding: K01 AA030083 (A.S.H.), T32 DA007261 (A.S.H.), DA54869 (A.A., J.G., H.E.), R01 DA54750 (A.A., R.B.), K02 DA32573 (A.A.), R21 AA027827 (R.B.), U01 DA055367 (R.B.), K01 DA51759 (E.C.J.), K23 MH121792 (N.R.K.), DP1 DA54394 (S.S.-R.), T32 MH014276 (G.A.P.), R01 AA027522 (A.E.), F31 AA029934 (S.E.P.), R01 MH120219 (E.M.T.-D., A.D.G.), RF1 AG073593 (E.M.T.-D., A.D.G.), P30 AG066614 (E.M.T.-D.), P2CHD042849 (E.M.T.-D.), R33 DA047527 (R.P., G.A.P.) and T32 AA028259 (J.D.D.)

Author information

Author notes

  1. These authors jointly supervised this work: Joel Gelernter, Howard J. Edenberg, Ryan Bogdan, Arpana Agrawal.

Authors and Affiliations

  1. Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA

    Alexander S. Hatoum, Sarah M. C. Colbert, Emma C. Johnson, Nicole R. Karcher, David A. A. Baranger, Laura J. Bierut, Kathleen K. Bucholz, Li-Shiun Chen, Louis Fox, Andrew C. Heath, Pamela A. F. Madden, Elliot C. Nelson, John P. Rice, Sarah M. Hartz & Arpana Agrawal

  2. Department of Psychology, Emory University, Atlanta, GA, USA

    Spencer B. Huggett

  3. Department of Psychiatry, Division of Human Genetics, Yale School of Medicine, New Haven, CT, USA

    Joseph D. Deak, Gita A. Pathak, Renato Polimanti & Joel Gelernter

  4. Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA

    Joseph D. Deak & Renato Polimanti

  5. Department of Psychiatry, UC San Diego School of Medicine, San Diego, CA, USA

    Mariela V. Jennings & Sandra Sanchez-Roige

  6. Department of Psychological and Brain Sciences, Washington University in Saint Louis, Saint Louis, MO, USA

    Sarah E. Paul, Isabella Hansen & Ryan Bogdan

  7. Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    Alexis Edwards

  8. Institute for Behavioral Genetics, University of Colorado-Boulder, Boulder, CO, USA

    Andrew D. Grotzinger

  9. Department of Psychology and Population Research Center, University of Texas at Austin, Austin, TX, USA

    Elliot M. Tucker-Drob

  10. Center for Studies of Addiction, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Henry R. Kranzler

  11. VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA

    Henry R. Kranzler

  12. Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Nashville, TN, USA

    Lea K. Davis & Sandra Sanchez-Roige

  13. Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA

    Lea K. Davis

  14. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA

    Lea K. Davis

  15. Department of Genetics, Yale School of Medicine, New Haven, CT, USA

    Joel Gelernter

  16. Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA

    Joel Gelernter

  17. Department of Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, IN, USA

    Tatiana M. Foroud, Dongbing Lai & Howard J. Edenberg

  18. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    Howard J. Edenberg

  19. Department of Psychiatry, University of Utah, Salt Lake City, UT, USA

    Daniel E. Adkins

  20. Department of Sociology, University of Utah, Salt Lake City, UT, USA

    Daniel E. Adkins

  21. Department of Psychology and College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, USA

    Amy E. Adkins

  22. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

    Mervi Alanne-Kinnunen, Jaakko Kaprio, Aarno Palotie, Teemu Palviainen & Samuli Ripatti

  23. Virginia Commonwealth University Alcohol Research Center, Richmond, VA, USA

    Jeffry C. Alexander, Silviu-Alin Bacanu, Kenneth S. Kendler, Brien P. Riley & Bradley T. Webb

  24. Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA

    Jeffry C. Alexander, Silviu-Alin Bacanu, Kenneth S. Kendler, Brien P. Riley & Bradley T. Webb

  25. Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA

    Jeffry C. Alexander, Silviu-Alin Bacanu, Kenneth S. Kendler, Brien P. Riley & Bradley T. Webb

  26. Department of Psychiatry Rutgers University, Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Fazil Aliev

  27. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA

    Anthony Batzler

  28. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA

    Joanna M. Biernacka

  29. Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, USA

    Tim B. Bigdeli

  30. Clinical Laboratory Investigations, Privolzhsky Research Medical University, Nizhny Novgorod, Russia

    Anna Blagonravova

  31. Department of Sociology, Institute of Behavioral Science, University of Colorado, Boulder, CO, USA

    Jason D. Boardman

  32. Department of Psychological Medicine, University of Otago, Christchurch, New Zealand

    Joseph M. Boden & John Horwood

  33. Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    Dorret I. Boomsma, Jouke Jan Hottenga, Lannie Ligthart & Hamdi Mbarek

  34. Department of Psychiatry and Psychology, University of California San Diego, La Jolla, CA, USA

    Sandra A. Brown

  35. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Danfeng Chen, Daniel Patrick Howrigan, Benjamin M. Neale, Aarno Palotie, Samuli Ripatti & Raymond K. Walters

  36. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

    Doo-Sup Choi

  37. NIH/NIAAA, Epidemiology and Biometry Branch, Bethesda, MD, USA

    S. Patricia Chou

  38. Human Genomics Research Group, Department of Biomedicine, University of Basel Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland

    Sven Cichon, Stefan Herms & Per Hoffmann

  39. Department of Psychiatry, University of Vermont, Burlington, VT, USA

    William E. Copeland

  40. Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA

    Robin P. Corley

  41. Institute of Human Genetics, University of Bonn, Bonn, Germany

    Franziska Degenhardt, Stefan Herms & Per Hoffmann

  42. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany

    Franziska Degenhardt, Stefan Herms & Per Hoffmann

  43. Social, Genetic and Developmental Psychiatry Centre Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Marta Di Forti & Diego Quattrone

  44. NIH/NIAAA, Office of the Clinical Director NIAAA Intramural Research Program, Bethesda, MD, USA

    Nancy Diazgranados

  45. Department of Psychiatry, Rutgers Addiction Research Center at the Brain Health Institute, Rutgers University, Robert Wood Johnson Medical School, Piscataway, NJ, USA

    Danielle M. Dick

  46. Graduate School of Education, Stanford University, Stanford, CA, USA

    Benjamin W. Domingue

  47. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland

    Johan G. Eriksson

  48. National Institute for Health and Welfare, Finland University of Helsinki, Helsinki, Finland

    Johan G. Eriksson

  49. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA

    Lindsay A. Farrer

  50. Departments of Neurology, Ophthalmology, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA

    Lindsay A. Farrer

  51. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Jerome C. Foo, Josef Frank, Marcella Rietschel, Fabian Streit, Jana Strohmaier, Stephanie Witt & Lea Zillich

  52. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA

    Mark A. Frye & Victor M. Karpyak

  53. LVR-Klinikum Düsseldorf, Heinrich-Heine-University Düsseldorf, Department of Psychiatry and Psychotherapy, University of Düsseldorf, Duesseldorf, Germany

    Wolfgang Gaebel

  54. Institute of Translational Biomedicine, Saint Petersburg State University, Saint Petersburg, Russia

    Raul R. Gainetdinov & Anastasia Levchenko

  55. Comprehensive Center of Clinical Neuroscience and Mental Health, Medical University of Vienna, Austria, Vienna, Austria

    Ina Giegling

  56. Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    Nathan A. Gillespie & Roseann E. Peterson

  57. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Alison M. Goate

  58. NIH/NIAAA, Laboratory of Neurogenetics, NIAAA, NIH, Rockville, MD, USA

    David Goldman

  59. NIH/NIAAA, Office of the Clinical Director, Rockville, MD, USA

    David Goldman

  60. Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    Scott Gordon, Nicholas G. Martin & John B. Whitfield

  61. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Laura M. Hack

  62. GenOmics, Bioinformatics, and Translational Research Center, RTI International Research, Triangle Park, NC, USA

    Dana B. Hancock

  63. Department of Sociology and Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Kathleen Mullan Harris

  64. Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria, Vienna, Austria

    Annette M. Hartmann, Bettina Konte & Dan Rujescu

  65. Institute of Human Genetics, University of Bonn School of Medicine and University Hospital Bonn, Bonn, Germany

    Stefanie Heilmann-Heimbach & Markus M. Nöthen

  66. Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA

    Victor Hesselbrock

  67. Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA

    John K. Hewitt

  68. Brain and Mind Centre, University of Sydney, Sydney, Australia

    Ian Hickie

  69. Laboratory of Neurogenetics, DICBR, NIAAA, NIH, USA, NIH/NIAAA, Laboratory of Neurogenetics, NIAAA, NIH, USA, Rockville, MD, USA

    Colin Hodgkinson & Pei-Hong Shen

  70. Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, USA

    Christian Hopfer

  71. Department of Medicine Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Daniel Patrick Howrigan

  72. Department of Psychology, University of Minnesota, Minneapolis, MN, USA

    William G. Iacono

  73. Max-Planck-Institute of Psychiatry, Munich, Germany

    Marcus Ising & Susanne Lucae

  74. GenOmics, Bioinformatics, and Translational Research Center Biostatistics and Epidemiology Division, RTI International, Fellows Program Research, Triangle Park, NC, USA

    Eric O. Johnson

  75. Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand

    Martin A. Kennedy

  76. Department of Psychology, University of Minnesota, Minneapolis, MN, USA

    Margaret Keyes, Matt McGue, Scott Vrieze & Stephanie Zellers

  77. Serbsky National Medical Research Center on Psychiatry and Addictions, Moscow, Russia

    Alexander Kibitov

  78. Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Falk Kiefer & Karl Mann

  79. Department of Psychiatry, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    John Kramer

  80. Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA

    Kenneth Krauter

  81. Addictions V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Saint Petersburg, Russia

    Evgeny M. Krupitsky

  82. Univeristy of Iowa Carver College of Medicine, Department of Psychiatry University of Iowa, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA

    Samuel Kuperman

  83. Department of Psychology and Logopedics Faculty of Medicine, University of Helsinki, Helsinki, Finland

    Jari Lahti & Marius Lahti-Pulkkinen

  84. Psychiatric Genetics QIMR Berghofer Medical Research Institute Brisbane, Queensland, Australia

    Penelope A. Lind & Sarah E. Medland

  85. Institute of Psychiatry, Psychology and Neuroscience, King’s College, London, UK

    Michael T. Lynskey

  86. Department of Human and Molecular Genetics and Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    Hermine H. Maes

  87. Department of Medical Epidemiology and Biostatistics, Karolinska Instituet, Stockholm, Sweden

    Patrik K. E. Magnusson & Nancy L. Pedersen

  88. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Brion S. Maher

  89. Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland

    Satu Männistö

  90. Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA

    Matthew B. McQueen

  91. Department of Psychiatry and Behavioral Sciences, Henri Begleiter Neurodynamics Laboratory, SUNY Downstate Medical Center, Brooklyn, NY, USA

    Jacquelyn L. Meyers

  92. The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia

    Grant W. Montgomery

  93. Department of Statistical Genetics, Max-Planck-Institute of Psychiatry, Munich, Germany

    Bertram Müller-Myhsok

  94. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Benjamin M. Neale, Aarno Palotie, Samuli Ripatti & Raymond K. Walters

  95. Stark Neurosciences Research Institute, Departments of Psychiatry and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    John I. Nurnberger

  96. Department of Medicine, Department of Neurology and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    Aarno Palotie

  97. University of Helsinki, Helsinki, Finland

    Aarno Palotie

  98. Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand

    John F. Pearson

  99. Department of Psychiatry, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands

    Brenda W. J. H. Penninx

  100. Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA

    Bernice Porjesz

  101. Martin-Luther-University Halle-Wittenberg, Department of Psychiatry, Psychotherapy and Psychosomatics, Halle (Saale), Germany

    Ulrich W. Preuss

  102. RKH Hospital Ludwigsburg, Department of Psychiatry, Psychotherapy and Psychosomatics, Ludwigsburg, Germany

    Ulrich W. Preuss

  103. Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland

    Katri Räikkönen

  104. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    Maureen D. Reynolds

  105. Department of Psychiatry and Psychotherapy, University of Regensburg Psychiatric Health Care Aargau, Regensburg, Germany

    Monika Ridinger

  106. Department of Public Health, University of Helsinki, Helsinki, Finland

    Samuli Ripatti

  107. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA

    Richard J. Rose

  108. V.M. Bekhterev National Medical Research Center for Psychiatry, Saint Petersburg, Russia

    Ksenia V. Rybakova

  109. Department of Quantitative Health Sciences, Divison of Computational Biology, Mayo Clinic, Rochester, MN, USA

    Euijung Ryu

  110. Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA

    Nancy L. Saccone

  111. Department of Psychiatry, Rutgers Biomedical and Health Sciences, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA

    Jessica E. Salvatore

  112. LVR-Hospital Essen, Department of Psychiatry and Psychotherapy Medical Faculty, University of Duisburg-Essen, Essen, Germany

    Norbert Scherbaum

  113. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Marc A. Schuckit

  114. Office of the Clinical Director NIH/NIAAA, Bethesda, MD, USA

    Melanie Schwandt

  115. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA

    Richard Sherva

  116. Department of Human and Molecular Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    Judy Silberg

  117. Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA

    Michael C. Stallings

  118. SAMRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa

    Dan J. Stein

  119. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    Ralph E. Tarter

  120. Department of Psychology and College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, USA

    Nathaniel Thomas

  121. Departments of Pharmaceutical Sciences, Psychiatry, and Human Genetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    Michael M. Vanyukov

  122. Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA

    Tamara L. Wall

  123. Sociology, Purdue University, West Lafayette, IN, USA

    Robbee Wedow

  124. Statistics, Purdue University, West Lafayette, IN, USA

    Robbee Wedow

  125. Medical and Molecular Genetics, Indiana University School of Medicine, West Lafayette, IN, USA

    Robbee Wedow

  126. AnalytiXIN, West Lafayette, IN, USA

    Robbee Wedow

  127. Computer Science, Purdue University, West Lafayette, IN, USA

    Robbee Wedow

  128. Department of Psychiatry, Division of Human Genetics, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT, USA

    Frank Wendt

  129. Department of Medical and Molecular Genetics, Division of Hereditary Genomics, School of Medicine, Indiana University, Indianapolis, IN, USA

    Leah Wetherill

  130. Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany

    Norbert Wodarz

  131. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia

    Margaret J. Wright

  132. Epidemiology and Biometry Branch, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

    Haitao Zhang

  133. Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA

    Hongyu Zhao

  134. Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT, USA

    Hang Zhou

  135. Department of Psychiatry, Psychiatric Hospital, Ludwig-Maximilians-University, Munich, Germany

    Peter Zill

Authors
  1. Alexander S. Hatoum
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  2. Sarah M. C. Colbert
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  3. Emma C. Johnson
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  4. Spencer B. Huggett
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  5. Joseph D. Deak
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  6. Gita A. Pathak
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  7. Mariela V. Jennings
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  8. Sarah E. Paul
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  9. Nicole R. Karcher
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  10. Isabella Hansen
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  11. David A. A. Baranger
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  12. Alexis Edwards
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  13. Andrew D. Grotzinger
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  14. Elliot M. Tucker-Drob
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  15. Henry R. Kranzler
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  16. Lea K. Davis
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  17. Sandra Sanchez-Roige
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  18. Renato Polimanti
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  19. Joel Gelernter
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  20. Howard J. Edenberg
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  21. Ryan Bogdan
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  22. Arpana Agrawal
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Consortia

Substance Use Disorder Working Group of the Psychiatric Genomics Consortium

  • Daniel E. Adkins
  • , Amy E. Adkins
  • , Mervi Alanne-Kinnunen
  • , Jeffry C. Alexander
  • , Fazil Aliev
  • , Silviu-Alin Bacanu
  • , Anthony Batzler
  • , Joanna M. Biernacka
  • , Laura J. Bierut
  • , Tim B. Bigdeli
  • , Anna Blagonravova
  • , Jason D. Boardman
  • , Joseph M. Boden
  • , Dorret I. Boomsma
  • , Sandra A. Brown
  • , Kathleen K. Bucholz
  • , Danfeng Chen
  • , Li-Shiun Chen
  • , Doo-Sup Choi
  • , S. Patricia Chou
  • , Sven Cichon
  • , William E. Copeland
  • , Robin P. Corley
  • , Franziska Degenhardt
  • , Marta Di Forti
  • , Nancy Diazgranados
  • , Danielle M. Dick
  • , Benjamin W. Domingue
  • , Johan G. Eriksson
  • , Lindsay A. Farrer
  • , Jerome C. Foo
  • , Tatiana M. Foroud
  • , Louis Fox
  • , Josef Frank
  • , Mark A. Frye
  • , Wolfgang Gaebel
  • , Raul R. Gainetdinov
  • , Ina Giegling
  • , Nathan A. Gillespie
  • , Alison M. Goate
  • , David Goldman
  • , Scott Gordon
  • , Laura M. Hack
  • , Dana B. Hancock
  • , Kathleen Mullan Harris
  • , Annette M. Hartmann
  • , Andrew C. Heath
  • , Stefanie Heilmann-Heimbach
  • , Stefan Herms
  • , Victor Hesselbrock
  • , John K. Hewitt
  • , Ian Hickie
  • , Colin Hodgkinson
  • , Per Hoffmann
  • , Christian Hopfer
  • , John Horwood
  • , Jouke Jan Hottenga
  • , Daniel Patrick Howrigan
  • , William G. Iacono
  • , Marcus Ising
  • , Eric O. Johnson
  • , Jaakko Kaprio
  • , Victor M. Karpyak
  • , Kenneth S. Kendler
  • , Martin A. Kennedy
  • , Margaret Keyes
  • , Alexander Kibitov
  • , Falk Kiefer
  • , Bettina Konte
  • , John Kramer
  • , Kenneth Krauter
  • , Evgeny M. Krupitsky
  • , Samuel Kuperman
  • , Jari Lahti
  • , Marius Lahti-Pulkkinen
  • , Dongbing Lai
  • , Anastasia Levchenko
  • , Lannie Ligthart
  • , Penelope A. Lind
  • , Susanne Lucae
  • , Michael T. Lynskey
  • , Pamela A. F. Madden
  • , Hermine H. Maes
  • , Patrik K. E. Magnusson
  • , Brion S. Maher
  • , Karl Mann
  • , Satu Männistö
  • , Nicholas G. Martin
  • , Hamdi Mbarek
  • , Matt McGue
  • , Matthew B. McQueen
  • , Sarah E. Medland
  • , Jacquelyn L. Meyers
  • , Grant W. Montgomery
  • , Bertram Müller-Myhsok
  • , Benjamin M. Neale
  • , Elliot C. Nelson
  • , Markus M. Nöthen
  • , John I. Nurnberger
  • , Aarno Palotie
  • , Teemu Palviainen
  • , John F. Pearson
  • , Nancy L. Pedersen
  • , Brenda W. J. H. Penninx
  • , Roseann E. Peterson
  • , Bernice Porjesz
  • , Ulrich W. Preuss
  • , Diego Quattrone
  • , Katri Räikkönen
  • , Maureen D. Reynolds
  • , John P. Rice
  • , Monika Ridinger
  • , Marcella Rietschel
  • , Brien P. Riley
  • , Samuli Ripatti
  • , Richard J. Rose
  • , Dan Rujescu
  • , Ksenia V. Rybakova
  • , Euijung Ryu
  • , Nancy L. Saccone
  • , Jessica E. Salvatore
  • , Norbert Scherbaum
  • , Marc A. Schuckit
  • , Melanie Schwandt
  • , Pei-Hong Shen
  • , Richard Sherva
  • , Judy Silberg
  • , Michael C. Stallings
  • , Dan J. Stein
  • , Fabian Streit
  • , Jana Strohmaier
  • , Ralph E. Tarter
  • , Nathaniel Thomas
  • , Michael M. Vanyukov
  • , Scott Vrieze
  • , Tamara L. Wall
  • , Raymond K. Walters
  • , Bradley T. Webb
  • , Robbee Wedow
  • , Frank Wendt
  • , Leah Wetherill
  • , John B. Whitfield
  • , Stephanie Witt
  • , Norbert Wodarz
  • , Margaret J. Wright
  • , Sarah M. Hartz
  • , Stephanie Zellers
  • , Haitao Zhang
  • , Hongyu Zhao
  • , Hang Zhou
  • , Peter Zill
  •  & Lea Zillich

Contributions

A.S.H. designed the study and conducted analyses. S.M.C.C., E.C.J., S.B.H., J.D.D., G.A.P., M.V.J., S.S.-R., S.E.P., N.R.K., I.H. and D.A.A.B. conducted various analyses. A.A., R.B., H.J.E. and J.G. supervised the study. A.D.G. and E.M.T.-D. provided statistical guidance. A.E., H.R.K., R.P., L.K.D. and S.S.-R. guided interpretation of key findings. A.S.H., H.J.E., J.G., R.B. and A.A. drafted the manuscript. A.S.H., S.M.C.C., J.D.D., M.V.J., S.E.P., N.R.K. and I.H. organized the data. The consortium members provided insight into various aspects of analyses and interpretation and data for some of the discovery GWAS that were inputs to these analyses. All named authors reviewed, edited and approved the submission.

Corresponding author

Correspondence to Alexander S. Hatoum.

Ethics declarations

Competing interests

H.R.K. is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals and Enthion Pharmaceuticals; a consultant to Sobrera Pharmaceuticals; and a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi and Otsuka. H.R.K. and J.G. hold US Patent 10900,082: ‘Genotype-guided dosing of opioid agonists’ issued on 26 January 2021. The remaining authors declare no competing interests.

Peer review

Peer review information

Nature Mental Health thanks Ditte Demontis and Eske Derks for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–10 and methods.

Reporting Summary

Supplementary Tables

Supplementary Tables 1–22.

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Hatoum, A.S., Colbert, S.M.C., Johnson, E.C. et al. Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders. Nat. Mental Health 1, 210–223 (2023). https://doi.org/10.1038/s44220-023-00034-y

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