Genome-wide association study implicates CHRNA2 in cannabis use disorder

Ditte Demontis; Veera Manikandan Rajagopal; Thorgeir E Thorgeirsson; Thomas D Als; Jakob Grove; Kalle Leppälä; Daniel F Gudbjartsson; Jonatan Pallesen; Carsten Hjorthøj; Gunnar W Reginsson; Thorarinn Tyrfingsson; Valgerdur Runarsdottir; Per Qvist; Jane Hvarregaard Christensen; Jonas Bybjerg-Grauholm; Marie Bækvad-Hansen; Laura M Huckins; Eli A Stahl; Allan Timmermann; Esben Agerbo; David M Hougaard; Thomas Werge; Ole Mors; Preben Bo Mortensen; Merete Nordentoft; Mark J Daly; Hreinn Stefansson; Kari Stefansson; Mette Nyegaard; Anders D Børglum

doi:10.1038/s41593-019-0416-1

Genome-wide association study implicates CHRNA2 in cannabis use disorder

Ditte Demontis, Veera Manikandan Rajagopal, Thorgeir E Thorgeirsson, Thomas D Als, Jakob Grove, Kalle Leppälä, Daniel F Gudbjartsson, Jonatan Pallesen, Carsten Hjorthøj, Gunnar W Reginsson, Thorarinn Tyrfingsson, Valgerdur Runarsdottir, Per Qvist, Jane Hvarregaard Christensen, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Laura M Huckins, Eli A Stahl, Allan Timmermann, Esben AgerboDavid M Hougaard, Thomas Werge, Ole Mors, Preben Bo Mortensen, Merete Nordentoft, Mark J Daly, Hreinn Stefansson, Kari Stefansson, Mette Nyegaard, Anders D Børglum

Institut for Klinisk Medicin

31 Citationer (Scopus)

Abstract

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 = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 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.

Originalsprog	Engelsk
Tidsskrift	Nature Neuroscience
Vol/bind	22
Udgave nummer	7
Sider (fra-til)	1066-1074
ISSN	1097-6256
DOI	https://doi.org/10.1038/s41593-019-0416-1
Status	Udgivet - 1 jul. 2019

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10.1038/s41593-019-0416-1

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Demontis, D., Rajagopal, V. M., Thorgeirsson, T. E., Als, T. D., Grove, J., Leppälä, K., Gudbjartsson, D. F., Pallesen, J., Hjorthøj, C., Reginsson, G. W., Tyrfingsson, T., Runarsdottir, V., Qvist, P., Christensen, J. H., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Huckins, L. M., Stahl, E. A., Timmermann, A., ... Børglum, A. D. (2019). Genome-wide association study implicates CHRNA2 in cannabis use disorder. Nature Neuroscience, 22(7), 1066-1074. https://doi.org/10.1038/s41593-019-0416-1

Demontis, D, Rajagopal, VM, Thorgeirsson, TE, Als, TD, Grove, J, Leppälä, K, Gudbjartsson, DF, Pallesen, J, Hjorthøj, C, Reginsson, GW, Tyrfingsson, T, Runarsdottir, V, Qvist, P, Christensen, JH, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Huckins, LM, Stahl, EA, Timmermann, A, Agerbo, E, Hougaard, DM, Werge, T, Mors, O, Mortensen, PB, Nordentoft, M, Daly, MJ, Stefansson, H, Stefansson, K, Nyegaard, M & Børglum, AD 2019, 'Genome-wide association study implicates CHRNA2 in cannabis use disorder', Nature Neuroscience, bind 22, nr. 7, s. 1066-1074. https://doi.org/10.1038/s41593-019-0416-1

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title = "Genome-wide association study implicates CHRNA2 in cannabis use disorder",

abstract = "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 = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 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.",

author = "Ditte Demontis and Rajagopal, {Veera Manikandan} and Thorgeirsson, {Thorgeir E} and Als, {Thomas D} and Jakob Grove and Kalle Lepp{\"a}l{\"a} and Gudbjartsson, {Daniel F} and Jonatan Pallesen and Carsten Hjorth{\o}j and Reginsson, {Gunnar W} and Thorarinn Tyrfingsson and Valgerdur Runarsdottir and Per Qvist and Christensen, {Jane Hvarregaard} and Jonas Bybjerg-Grauholm and Marie B{\ae}kvad-Hansen and Huckins, {Laura M} and Stahl, {Eli A} and Allan Timmermann and Esben Agerbo and Hougaard, {David M} and Thomas Werge and Ole Mors and Mortensen, {Preben Bo} and Merete Nordentoft and Daly, {Mark J} and Hreinn Stefansson and Kari Stefansson and Mette Nyegaard and B{\o}rglum, {Anders D}",

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T1 - Genome-wide association study implicates CHRNA2 in cannabis use disorder

AU - Demontis, Ditte

AU - Rajagopal, Veera Manikandan

AU - Thorgeirsson, Thorgeir E

AU - Als, Thomas D

AU - Grove, Jakob

AU - Leppälä, Kalle

AU - Gudbjartsson, Daniel F

AU - Pallesen, Jonatan

AU - Hjorthøj, Carsten

AU - Reginsson, Gunnar W

AU - Tyrfingsson, Thorarinn

AU - Runarsdottir, Valgerdur

AU - Qvist, Per

AU - Christensen, Jane Hvarregaard

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-Hansen, Marie

AU - Huckins, Laura M

AU - Stahl, Eli A

AU - Timmermann, Allan

AU - Agerbo, Esben

AU - Hougaard, David M

AU - Werge, Thomas

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - Nordentoft, Merete

AU - Daly, Mark J

AU - Stefansson, Hreinn

AU - Stefansson, Kari

AU - Nyegaard, Mette

AU - Børglum, Anders D

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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 = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 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.

AB - 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 = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 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.

U2 - 10.1038/s41593-019-0416-1

DO - 10.1038/s41593-019-0416-1

M3 - Journal article

C2 - 31209380

SN - 1097-6256

VL - 22

SP - 1066

EP - 1074

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 7

ER -

Genome-wide association study implicates CHRNA2 in cannabis use disorder

Abstract

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