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

Research output: Contribution to journal › Article › peer-review

87 Scopus citations

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
State	Published - Mar 2023
Externally published	Yes

Funding

Funders	Funder number
Health Services Research and Development
Office of Research and Development
Vanderbilt University Medical Center	UL1TR000445, S10RR025141, UL1RR024975, UL1TR002243
Cold Harbor Labroatory	U01 DA055367, K02 DA32573, R01 AA027522, R21 AA027827, R01 MH120219, T32 MH014276, T32 AA028259, DA54869, P30 AG066614, K01 AA030083, T32 DA007261, DP1 DA54394, R01 DA54750, RF1 AG073593, K01 DA51759, R33 DA047527, K23 MH121792, F31 AA029934, P2CHD042849
U.S. Department of Veterans Affairs	G002

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s44220-023-00034-y

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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 Rose, {Richard J.}",

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 = "אנגלית",

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.

AU - Paul, Sarah E.

AU - Karcher, Nicole R.

AU - Hansen, Isabella

AU - Baranger, David A.A.

AU - Edwards, Alexis

AU - Grotzinger, Andrew D.

AU - Zillich, Lea

AU - Zill, Peter

AU - Zhou, Hang

AU - Zhao, Hongyu

AU - Zhang, Haitao

AU - Zellers, Stephanie

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 - Rose, Richard J.

PY - 2023/3

Y1 - 2023/3

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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AN - SCOPUS:85218232859

SN - 2731-6076

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JO - Nature Mental Health

JF - Nature Mental Health

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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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