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

被引：91

作者：

Hatoum, Alexander S. ^{[1
]}

Colbert, Sarah M. C. ^{[1
]}

Johnson, Emma C. ^{[1
]}

Huggett, Spencer B. ^{[2
]}

Deak, Joseph D. ^{[3
,4
]}

Pathak, Gita A. ^{[3
]}

Jennings, Mariela V. ^{[5
]}

Paul, Sarah E. ^{[6
]}

Karcher, Nicole R. ^{[1
]}

Hansen, Isabella ^{[6
]}

Baranger, David A. A. ^{[1
]}

Edwards, Alexis ^{[7
]}

Grotzinger, Andrew D. ^{[8
]}

Tucker-Drob, Elliot M. ^{[9
,10
]}

Kranzler, Henry R. ^{[11
,12
]}

Davis, Lea K. ^{[13
,14
,15
]}

Sanchez-Roige, Sandra ^{[13
]}

Polimanti, Renato

Gelernter, Joel ^{[16
,17
]}

Edenberg, Howard J. ^{[18
,19
]}

Bogdan, Ryan

Agrawal, Arpana

Substance Use Disorder Working Group of the Psychiatric Genomics Consortium

机构：

[1] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63130 USA

[2] Emory Univ, Dept Psychol, Atlanta, GA USA

[3] Yale Sch Med, Div Human Genet, Dept Psychiat, New Haven, CT USA

[4] Vet Affairs Connecticut Healthcare Syst, West Haven, CT USA

[5] Univ Calif San Diego, Sch Med, Dept Psychiat, San Diego, CA USA

[6] Washington Univ St Louis, Dept Psychol & Brain Sci, St Louis, MO USA

[7] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA

[8] Univ Colorado, Boulder Inst Behav Genet, Boulder, CO USA

[9] Univ Texas Austin, Dept Psychol, Populat Res Ctr, Austin, TX 78712 USA

[10] Univ Texas Austin, Populat Res Ctr, Austin, TX USA

[11] Univ Penn Perelman Sch Med, Ctr Studies Addict, Dept Psychiat, Dept Psychiat, Philadelphia, PA USA

[12] Crescenz VAMC, VISN MIRECC 4, Philadelphia, PA USA

[13] Vanderbilt Univ, Dept Med, Div Genet Med, Nashville, TN USA

[14] Vanderbilt Univ, Med Ctr, Dept Psychiat & Behav Sci, Nashville, TN USA

[15] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA

[16] Yale Sch Med, Dept Genet, New Haven, CT USA

[17] Yale Sch Med, Dept Neurosci, New Haven, CT USA

[18] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN USA

[19] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN USA

来源：

NATURE MENTAL HEALTH | 2023年 / 1卷 / 03期

关键词：

CANNABIS USE; DEPENDENCE; ALCOHOL; BIOBANK; HEALTH; COMMON;

D O I：

10.1038/s44220-023-00034-y

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

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 x 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.

引用

页码：210 / 223

页数：17

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