Genome-wide association study implicates CHRNA2 in cannabis use disorder

被引：80

作者：

Demontis, Ditte ^{[1
,2
,3
,4
]}

Rajagopal, Veera Manikandan ^{[1
,2
,3
,4
]}

Thorgeirsson, Thorgeir E. ^{[5
]}

Als, Thomas D. ^{[1
,2
,3
,4
]}

Grove, Jakob ^{[1
,2
,3
,4
,6
]}

Leppala, Kalle ^{[1
,2
,3
,4
]}

Gudbjartsson, Daniel F. ^{[5
]}

Pallesen, Jonatan ^{[1
,2
,3
,4
]}

Hjorthoj, Carsten ^{[3
,7
]}

Reginsson, Gunnar W. ^{[5
]}

Tyrfingsson, Thorarinn ^{[8
]}

Runarsdottir, Valgerdur ^{[8
]}

Qvist, Per ^{[1
,2
,3
,4
]}

Christensen, Jane Hvarregaard ^{[1
,2
,3
,4
]}

Bybjerg-Grauholm, Jonas ^{[3
,9
]}

Baekvad-Hansen, Marie ^{[3
,9
]}

Huckins, Laura M. ^{[10
,11
]}

Stahl, Eli A. ^{[10
,11
]}

Timmermann, Allan ^{[12
]}

Agerbo, Esben ^{[3
,12
,13
]}

Hougaard, David M. ^{[3
,9
]}

Werge, Thomas ^{[3
,14
,15
]}

Mors, Ole ^{[3
,16
]}

Mortensen, Preben Bo ^{[3
,12
,13
]}

Nordentoft, Merete ^{[3
,7
,17
]}

Daly, Mark J. ^{[18
,19
,20
,21
]}

Stefansson, Hreinn ^{[5
]}

Stefansson, Kari ^{[5
]}

Nyegaard, Mette ^{[1
,2
,3
]}

Borglum, Anders D. ^{[1
,2
,3
,4
]}

机构：

[1] Aarhus Univ, Dept Biomed Human Genet, Aarhus, Denmark

[2] Aarhus Univ, Ctr Integrat Sequencing, Aarhus, Denmark

[3] Lundbeck Fdn Initiat Integrat Psychiat Res, Aarhus, Denmark

[4] Ctr Genom & Personalized Med, Aarhus, Denmark

[5] deCODE Genet Amgen, Reykjavik, Iceland

[6] Aarhus Univ, Bioinformat Res Ctr, Aarhus, Denmark

[7] Copenhagen Univ Hosp, Mental Hlth Ctr Copenhagen, Mental Hlth Serv Capital Reg Denmark, Hellerup, Denmark

[8] Vogur Hosp, Natl Ctr Addict Med SAA, Reykjavik, Iceland

[9] Statens Serum Inst, Ctr Neonatal Screening, Dept Congenital Disorders, Copenhagen, Denmark

[10] Icahn Sch Med Mt Sinai, Div Psychiat Genom, New York, NY 10029 USA

[11] Icahn Sch Med Mt Sinai, Dept Genet & Genom, New York, NY 10029 USA

[12] Aarhus Univ, Natl Ctr Register Based Res, Aarhus, Denmark

[13] Aarhus Univ, Ctr Integrated Register Based Res, Aarhus, Denmark

[14] Mental Hlth Serv Copenhagen, Inst Biol Psychiat, MHC Sct Hans, Roskilde, Denmark

[15] Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark

[16] Aarhus Univ Hosp, Psychosis Res Unit, Risskov, Denmark

[17] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark

[18] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[19] Harvard Med Sch, Boston, MA 02115 USA

[20] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[21] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

来源：

NATURE NEUROSCIENCE | 2019年 / 22卷 / 07期

基金：

欧盟地平线“2020”; 美国国家卫生研究院;

关键词：

POLYGENIC RISK; USE INITIATION; PSYCHIATRIC-DISORDERS; MARIJUANA USE; METAANALYSIS; SCHIZOPHRENIA; NICOTINE; LOCI; HERITABILITY; ACTIVATION;

D O I：

10.1038/s41593-019-0416-1

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P =9.31x 10(-12)) that replicates in an independent population (P-replication = 3.27 x 10(- 3), Pmeta-analysis = 9.09 x 10(-12)). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic alpha 2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.

引用

页码：1066 / +

页数：12

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