Preprint open access publication

Genome-wide association study implicates CHRNA2 in cannabis use disorder

bioRxiv, Cold Spring Harbor Laboratory,


DOI:10.1101/237321, Dimensions: pub.1099920458,



  1. (1) Lundbeck Foundation, grid.452548.a
  2. (2) Aarhus University, grid.7048.b, AU
  3. (3) Copenhagen University Hospital, Mental Health Centre Copenhagen Mental Health Services in the Capital Region of Denmark, Hellerup, Denmark
  4. (4) State Serum Institute, grid.6203.7
  5. (5) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  6. (6) Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
  7. (7) University of Copenhagen, grid.5254.6, KU
  8. (8) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  9. (9) Broad Institute, grid.66859.34
  10. (10) Massachusetts General Hospital, grid.32224.35


Introductory paragraph Cannabis is the most frequently used illicit psychoactive substance worldwide 1 . Life time use has been reported among 35-40% of adults in Denmark 2 and the United States 3 . Cannabis use is increasing in the population 4–6 and among users around 9% become dependent 7 . The genetic risk component is high with heritability estimates of 51 8 –70% 9 . Here we report the first genome-wide significant risk locus for cannabis use disorder (CUD, P=9.31×10 −12 ) that replicates in an independent population (P replication =3.27×10 −3 , P metaanalysis =9.09×10 −12 ). The finding is based on a genome-wide association study (GWAS) of 2,387 cases and 48,985 controls followed by replication in 5,501 cases and 301,041 controls. The index SNP (rs56372821) is a strong eQTL for CHRNA2 and analyses of the genetic regulated gene expressions identified significant association of CHRNA2 expression in cerebellum with CUD. This indicates a potential therapeutic use in CUD of compounds with agonistic effect on the neuronal acetylcholine receptor alpha-2 subunit encoded by CHRNA2 . At the polygenic level analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance.


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