Genome-wide association study implicates CHRNA2 in cannabis use disorder

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  • Ditte Demontis
  • Veera Manikandan Rajagopal
  • Thorgeir E. Thorgeirsson, DeCODE Genetics/Amgen
  • ,
  • Thomas D. Als
  • Jakob Grove
  • Kalle Leppälä
  • Daniel F. Gudbjartsson, DeCODE Genetics/Amgen
  • ,
  • Jonatan Pallesen, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Center for Genomics and Personalized Medicine, Aarhus, Denmark.
  • ,
  • Carsten Hjorthøj, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Københavns Universitet, Capital Region of Denmark
  • ,
  • Gunnar W. Reginsson, DeCODE Genetics/Amgen
  • ,
  • Thorarinn Tyrfingsson, Vogur Hospital
  • ,
  • Valgerdur Runarsdottir, Vogur Hospital
  • ,
  • Per Qvist
  • Jane Hvarregaard Christensen
  • Jonas Bybjerg-Grauholm, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Statens Serum Institut
  • ,
  • Marie Bækvad-Hansen, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Statens Serum Institut
  • ,
  • Laura M. Huckins, Icahn School of Medicine at Mount Sinai
  • ,
  • Eli A. Stahl, Icahn School of Medicine at Mount Sinai
  • ,
  • Allan Timmermann
  • Esben Agerbo
  • David M. Hougaard, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Statens Serum Institut
  • ,
  • Thomas Werge, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Mental Health Services Copenhagen, Københavns Universitet
  • ,
  • Ole Mors
  • Preben Bo Mortensen
  • Merete Nordentoft, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Københavns Universitet
  • ,
  • Mark J. Daly, Massachusetts General Hospital, Boston, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • ,
  • Hreinn Stefansson, DeCODE Genetics/Amgen
  • ,
  • Kari Stefansson, DeCODE Genetics/Amgen
  • ,
  • 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.

OriginalsprogEngelsk
TidsskriftNature Neuroscience
Vol/bind22
Sider (fra-til)1066-1074
Antal sider9
ISSN1097-6256
DOI
StatusUdgivet - jun. 2019

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