GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia

被引：308

作者：

Pasman, Joelle A. ^{[1
]}

Verweij, Karin J. H. ^{[1
,2
]}

Gerring, Zachary ^{[3
,4
,5
]}

Stringer, Sven ^{[6
]}

Sanchez-Roige, Sandra ^{[7
]}

Treur, Jorien L. ^{[8
]}

Abdellaoui, Abdel ^{[2
]}

Nivard, Michel G. ^{[9
]}

Baselmans, Bart M. L. ^{[9
]}

Ong, Jue-Sheng ^{[3
,4
,5
]}

Ip, Hill F. ^{[9
]}

van der Zee, Matthijs D. ^{[9
]}

Bartels, Meike ^{[9
]}

Day, Felix R. ^{[10
]}

Fontanillas, Pierre ^{[11
]}

Elson, Sarah L. ^{[11
]}

de Wit, Harriet ^{[12
]}

Davis, Lea K. ^{[13
]}

MacKillop, James ^{[14
,15
]}

Derringer, Jaime L. ^{[16
]}

Branje, Susan J. T. ^{[17
]}

Hartman, Catharina A. ^{[18
]}

Heath, Andrew C. ^{[19
]}

van Lier, Pol A. C. ^{[20
,21
]}

Madden, Pamela A. F. ^{[19
]}

Maegi, Reedik ^{[22
]}

Meeus, Wim ^{[17
]}

Montgomery, Grant W. ^{[23
]}

Oldehinkel, A. J. ^{[18
]}

Pausova, Zdenka ^{[24
]}

Ramos-Quiroga, Josep A. ^{[25
,26
,27
,28
]}

Paus, Tomas ^{[29
,30
,31
]}

Ribases, Marta ^{[25
,26
,27
]}

Kaprio, Jaakko ^{[32
]}

Boks, Marco P. M. ^{[33
]}

Bell, Jordana T. ^{[34
]}

Spector, Tim D. ^{[34
]}

Gelernter, Joel ^{[35
]}

Boomsma, Dorret I. ^{[9
]}

Martin, Nicholas G. ^{[3
,4
,5
]}

MacGregor, Stuart ^{[3
,4
,5
]}

Perry, John R. B. ^{[10
]}

Palmer, Abraham A. ^{[7
,36
]}

Posthuma, Danielle ^{[6
]}

Munafo, Marcus R. ^{[8
,37
,38
]}

Gillespie, Nathan A. ^{[3
,4
,5
,39
]}

Derks, Eske M. ^{[3
,4
,5
]}

Vink, Jacqueline M. ^{[1
]}

机构：

[1] Radboud Univ Nijmegen, Behav Sci Inst, Nijmegen, Netherlands

[2] Univ Amsterdam, Amsterdam UMC, Dept Psychiat, Amsterdam, Netherlands

[3] QIMR Berghofer Med Res Inst, Genet Epidemiol Lab, Brisbane, Qld, Australia

[4] QIMR Berghofer Med Res Inst, Stat Genet Lab, Brisbane, Qld, Australia

[5] QIMR Berghofer Med Res Inst, Translat Neurogen Lab, Brisbane, Qld, Australia

[6] Vrije Univ Amsterdam, Ctr Neurogenom & Cognit Res, Dept Complex Trait Genet, Amsterdam, Netherlands

[7] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[8] Univ Bristol, MRC Integrat Epidemiol Unit IEU, Bristol, Avon, England

[9] Vrije Univ Amsterdam, Netherlands Twin Register, Dept Biol Psychol, Amsterdam, Netherlands

[10] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England

[11] 23andMe Inc, Mountain View, CA USA

[12] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA

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

[14] McMaster Univ, St Josephs Healthcare Hamilton, Peter Boris Ctr Addict Res, Hamilton, ON, Canada

[15] McMaster Univ, St Josephs Healthcare Hamilton, Michael G DeGroote Ctr Med Cannabis Res, Hamilton, ON, Canada

[16] Univ Illinois, Dept Psychol, Champaign, IL USA

[17] Univ Utrecht, Dept Youth & Family, Utrecht, Netherlands

[18] Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, Groningen, Netherlands

[19] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[20] Vrije Univ Amsterdam, Dept Dev Psychol, Amsterdam, Netherlands

[21] Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands

[22] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia

[23] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[24] Hosp Sick Children, Toronto, ON, Canada

[25] Univ Autonoma Barcelona, Vall dHebron Res Inst VHIR, Grp Psychiat Mental Hlth & Addict, Psychiat Genet Unit, Barcelona, Spain

[26] Hosp Univ Vall dHebron, Dept Psychiat, Barcelona, Spain

[27] Inst Salud Carlos III, Biomed Network Res Ctr Mental Hlth CIBERSAM, Barcelona, Spain

[28] Univ Autonoma Barcelona, Dept Psychiat & Legal Med, Barcelona, Spain

[29] Baycrest, Rotman Res Inst, Toronto, ON, Canada

[30] Univ Toronto, Dept Psychol, Toronto, ON, Canada

[31] Univ Toronto, Dept Psychiat, Toronto, ON, Canada

[32] Univ Helsinki, Inst Mol Med Finland FIMM, HiLIFE Unit, Helsinki, Finland

[33] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, Utrecht, Netherlands

[34] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England

[35] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA

[36] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA

[37] Univ Bristol, UK Ctr Tobacco & Alcohol Studies, Bristol, Avon, England

[38] Univ Bristol, Sch Expt Psychol, Bristol, Avon, England

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

来源：

NATURE NEUROSCIENCE | 2018年 / 21卷 / 09期

基金：

欧盟地平线“2020”; 澳大利亚研究理事会; 美国国家卫生研究院; 芬兰科学院; 欧洲研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; CELL-ADHESION MOLECULES; MENDELIAN RANDOMIZATION; USE INITIATION; SUBSTANCE USE; NCAM1; METAANALYSIS; VARIANTS; NICOTINE; ALCOHOL;

D O I：

10.1038/s41593-018-0206-1

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested sub-stance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

引用

页码：1161 / +

页数：12

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