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Genome-wide association study implicates CHRNA2 in cannabis use disorder

Authors :: Kalle Leppälä
Ditte Demontis
Ole Mors
Thorarinn Tyrfingsson
Laura M. Huckins
Anders D. Børglum
Kari Stefansson
Mark J. Daly
David M. Hougaard
Carsten Hjorthøj
Daniel F. Gudbjartsson
Gunnar W Reginsson
Thomas Werge
Jane H. Christensen
Per Qvist
Eli A. Stahl
Hreinn Stefansson
Allan Timmermann
Valgerdur Runarsdottir
Thorgeir E. Thorgeirsson
Jonatan Pallesen
Esben Agerbo
Jonas Bybjerg-Grauholm
Merete Nordentoft
Jakob Grove
Preben Bo Mortensen
Marie Bækvad-Hansen
Mette Nyegaard
Veera M. Rajagopal
Thomas Damm Als
Source :: Nature Neuroscience, 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, Agerbo, E, Hougaard, D M, Werge, T, Mors, O, Mortensen, P B, Nordentoft, M, Daly, M J, Stefansson, H, Stefansson, K, Nyegaard, M & Børglum, A D 2019, ' Genome-wide association study implicates CHRNA2 in cannabis use disorder ' Nature Neuroscience . https://doi.org/10.1038/s41593-019-0416-1, 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, Agerbo, E, Hougaard, D M, Werge, T, Mors, O, Mortensen, P B, Nordentoft, M, Daly, M J, Stefansson, H, Stefansson, K, Nyegaard, M & Børglum, A D 2019, ' Genome-wide association study implicates CHRNA2 in cannabis use disorder ', Nature Neuroscience, vol. 22, no. 7, pp. 1066-1074 . https://doi.org/10.1038/s41593-019-0416-1, Nat Neurosci, 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, Agerbo, E, Hougaard, D M, Werge, T, Mors, O, Mortensen, P B, Nordentoft, M, Daly, M J, Stefansson, H, Stefansson, K, Nyegaard, M & Børglum, A D 2019, ' Genome-wide association study implicates CHRNA2 in cannabis use disorder ', Nature Neuroscience, vol. 22, pp. 1066-1074 . https://doi.org/10.1038/s41593-019-0416-1
Publication Year :: 2019
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. The study reports a genome-wide significant locus for cannabis use disorder, replicating in an independent cohort, and implicates CHRNA2, which encodes an acetylcholine receptor subunit, in the disorder by analyses of genetically regulated gene expression.