Genome-wide association study implicates CHRNA2 in cannabis use disorder

Ditte Demontis, Veera Manikandan Rajagopal, Thomas D. Als, Jakob Grove, Jonatan Pallesen, Carsten Hjorthøj, Per Qvist, Jane Hvarregaard Christensen, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Laura M. Huckins, Eli A. Stahl, Allan Timmermann, Esben Agerbo, David M. Hougaard, Thomas Werge, Ole Mors, Preben Bo Mortensen, Merete Nordentoft, Mark DalyMette Nyegaard, Anders D. Børglum

Publikation: Working paper/PreprintPreprint

Abstrakt

Cannabis is the most frequently used illicit psychoactive substance worldwide1. Life time use has been reported among 35-40% of adults in Denmark2 and the United States3. Cannabis use is increasing in the population4–6 and among users around 9% become dependent7. The genetic risk component is high with heritability estimates of 518–70%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 (Preplication=3.27×10−3, Pmetaanalysis=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.

OriginalsprogEngelsk
UdgiverbioRxiv
DOI
StatusUdgivet - 21 dec. 2017
Udgivet eksterntJa

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