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

Substance Use Disorder Working Group of the Psychiatric Genomics Consortium

doi:10.1038/s44220-023-00034-y

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

Substance Use Disorder Working Group of the Psychiatric Genomics Consortium

Washington University St. Louis
Emory University
Yale University
Department of Veterans Affairs
University of California at San Diego
Virginia Commonwealth University
University of Colorado Boulder
Heidelberg University
Ludwig Maximilian University of Munich
National Institutes of Health
University of Minnesota Twin Cities
University of Queensland
University of Regensburg
Queensland Institute of Medical Research
Indiana University
Purdue University
Indiana University Bloomington
AnalytiXIN
Department of Computer Science
Broad Institute
Massachusetts General Hospital
University of Pittsburgh
University of Cape Town
Boston University
University of Duisburg-Essen
UMDNJ-Robert Wood Johnson Medical School
Mayo Clinic Rochester, MN
V.M. Bekhterev National Medical Research Center for Psychiatry
Medical University of Vienna
Vrije Universiteit Amsterdam
University of Helsinki
King's College London
Martin Luther University Halle-Wittenberg
RKH Hospital Ludwigsburg
SUNY Downstate Health Sciences University
Karolinska Institutet
University of Otago
University of Bonn
Max Planck Institute of Psychiatry
National Institute for Health and Welfare
Heidelberg University
Johns Hopkins University
St. Petersburg State University
University of Iowa
St. Petersburg Bekhterev Psychoneurological Research Institute
Serbsky National Medical Research Center on Psychiatry and Addictions
RTI International
University of Colorado Anschutz Medical Campus
University of Basel
University of Sydney
University of Connecticut
University of North Carolina at Chapel Hill
Stanford University
Icahn School of Medicine at Mount Sinai
Heinrich Heine University Düsseldorf
Rutgers - The State University of New Jersey, New Brunswick
University of Vermont
Mayo Clinic College of Medicine and Science
Privolzhskiy Research Medical University
University of Utah
University of Texas at Austin
University of Pennsylvania
VA Medical Center
Vanderbilt University

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136 Citations (Scopus)

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.

Original language	English
Article number	1499
Pages (from-to)	210-223
Number of pages	14
Journal	Nature Mental Health
Volume	1
Issue number	3
DOIs	https://doi.org/10.1038/s44220-023-00034-y
Publication status	Published - Mar 2023
Externally published	Yes

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10.1038/s44220-023-00034-y

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@article{1f51faffad50488294219fd30eb2b8ac,

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

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.",

author = "\{Substance Use Disorder Working Group of the Psychiatric Genomics Consortium\} and Hatoum, \{Alexander S.\} and Colbert, \{Sarah M.C.\} and Johnson, \{Emma C.\} and Huggett, \{Spencer B.\} and Deak, \{Joseph D.\} and Pathak, \{Gita A.\} and Jennings, \{Mariela V.\} and Paul, \{Sarah E.\} and Karcher, \{Nicole R.\} and Isabella Hansen and Baranger, \{David A.A.\} and Alexis Edwards and Grotzinger, \{Andrew D.\} and Lea Zillich and Peter Zill and Hang Zhou and Hongyu Zhao and Haitao Zhang and Stephanie Zellers and Hartz, \{Sarah M.\} and Wright, \{Margaret J.\} and Norbert Wodarz and Stephanie Witt and Whitfield, \{John B.\} and Leah Wetherill and Frank Wendt and Robbee Wedow and Webb, \{Bradley T.\} and Walters, \{Raymond K.\} and Wall, \{Tamara L.\} and Scott Vrieze and Vanyukov, \{Michael M.\} and Nathaniel Thomas and Tarter, \{Ralph E.\} and Jana Strohmaier and Fabian Streit and Stein, \{Dan J.\} and Stallings, \{Michael C.\} and Judy Silberg and Richard Sherva and Shen, \{Pei Hong\} and Melanie Schwandt and Schuckit, \{Marc A.\} and Norbert Scherbaum and Salvatore, \{Jessica E.\} and Saccone, \{Nancy L.\} and Euijung Ryu and Rybakova, \{Ksenia V.\} and Dan Rujescu and Hottenga, \{Jouke Jan\}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2023.",

year = "2023",

month = mar,

doi = "10.1038/s44220-023-00034-y",

language = "English",

volume = "1",

pages = "210--223",

journal = "Nature Mental Health",

issn = "2731-6076",

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AU - Substance Use Disorder Working Group of the Psychiatric Genomics Consortium

AU - Hatoum, Alexander S.

AU - Colbert, Sarah M.C.

AU - Johnson, Emma C.

AU - Huggett, Spencer B.

AU - Deak, Joseph D.

AU - Pathak, Gita A.

AU - Jennings, Mariela V.

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AU - Baranger, David A.A.

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AU - Zillich, Lea

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AU - Zhang, Haitao

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AU - Hartz, Sarah M.

AU - Wright, Margaret J.

AU - Wodarz, Norbert

AU - Witt, Stephanie

AU - Whitfield, John B.

AU - Wetherill, Leah

AU - Wendt, Frank

AU - Wedow, Robbee

AU - Webb, Bradley T.

AU - Walters, Raymond K.

AU - Wall, Tamara L.

AU - Vrieze, Scott

AU - Vanyukov, Michael M.

AU - Thomas, Nathaniel

AU - Tarter, Ralph E.

AU - Strohmaier, Jana

AU - Streit, Fabian

AU - Stein, Dan J.

AU - Stallings, Michael C.

AU - Silberg, Judy

AU - Sherva, Richard

AU - Shen, Pei Hong

AU - Schwandt, Melanie

AU - Schuckit, Marc A.

AU - Scherbaum, Norbert

AU - Salvatore, Jessica E.

AU - Saccone, Nancy L.

AU - Ryu, Euijung

AU - Rybakova, Ksenia V.

AU - Rujescu, Dan

AU - Hottenga, Jouke Jan

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N2 - 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.

AB - 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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DO - 10.1038/s44220-023-00034-y

M3 - Article

AN - SCOPUS:85218232859

SN - 2731-6076

VL - 1

SP - 210

EP - 223

JO - Nature Mental Health

JF - Nature Mental Health

IS - 3

M1 - 1499

ER -

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

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