Department of Economics and Business Economics

Genome-wide association study implicates CHRNA2 in cannabis use disorder

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Ditte Demontis
  • Veera Manikandan Rajagopal
  • Thorgeir E Thorgeirsson, deCODE Genetics/Amgen inc., Reykjavik, 101, Iceland.
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  • Thomas D Als
  • Jakob Grove
  • Kalle Leppälä
  • Daniel F Gudbjartsson, deCODE Genetics/Amgen inc., Reykjavik, 101, Iceland.
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  • Jonatan Pallesen
  • Carsten Hjorthøj, Child and Adolescent Mental Health Centre, Mental Health Services Capital Region, Research Unit, Copenhagen University Hospital, Copenhagen, Denmark; Mental Health Centre Copenhagen, Copenhagen University Hospital, Mental Health Services Capital Region, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.
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  • Gunnar W Reginsson, deCODE Genetics/Amgen inc., Reykjavik, 101, Iceland.
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  • Thorarinn Tyrfingsson, National Center of Addiction Medicine (SAA), Vogur Hospital, Reykjavík, Iceland.
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  • Valgerdur Runarsdottir, National Center of Addiction Medicine (SAA), Vogur Hospital, Reykjavík, Iceland.
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  • Per Qvist
  • Jane Hvarregaard Christensen
  • Jonas Bybjerg-Grauholm, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, 2300, Denmark.
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  • Marie Bækvad-Hansen, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, 2300, Denmark.
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  • Laura M Huckins, Department of Genetics and Genomic Science, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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  • Eli A Stahl, Department of Genetics and Genomic Science, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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  • Allan Timmermann
  • Esben Agerbo
  • David M Hougaard, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, 2300, Denmark.
  • ,
  • Thomas Werge, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark.
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  • Ole Mors
  • Preben Bo Mortensen
  • Merete Nordentoft, l Department of Clinical Medicine, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark.
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  • Mark J Daly, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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  • Hreinn Stefansson, deCODE Genetics/Amgen inc., Reykjavik, 101, Iceland.
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  • Kari Stefansson, deCODE Genetics/Amgen inc., Reykjavik, 101, Iceland.
  • ,
  • 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.

Original languageEnglish
JournalNature Neuroscience
ISSN1097-6256
DOIs
Publication statusE-pub ahead of print - 17 Jun 2019

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