Genome-wide association study implicates CHRNA2 in cannabis use disorder

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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 & 10 andre David M Hougaard, Thomas Werge, Ole Mors, Preben Bo Mortensen, Merete Nordentoft, Mark J Daly, Hreinn Stefansson, Kari Stefansson, Mette Nyegaard, Anders D Børglum

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.

TidsskriftNature Neuroscience
Udgave nummer7
Sider (fra-til)1066-1074
StatusUdgivet - 2019

ID: 224337777