PT  - JOURNAL ARTICLE
AU  - Ditte Demontis
AU  - Veera Manikandan Rajagopal
AU  - Thorgeir E. Thorgeirsson
AU  - Thomas D. Als
AU  - Jakob Grove
AU  - Jonatan Pallesen
AU  - Carsten Hjorthøj
AU  - Gunnar W. Reginsson
AU  - Thorarinn Tyrfingsson
AU  - Valgerdur Runarsdottir
AU  - Per Qvist
AU  - Jane Hvarregaard Christensen
AU  - Laura M. Huckins
AU  - Eli A. Stahl
AU  - Allan Timmermann
AU  - Esben Agerbo
AU  - Thomas Werge
AU  - Ole Mors
AU  - Preben Bo Mortensen
AU  - Merete Nordentoft
AU  - Mark Daly
AU  - Hreinn Stefansson
AU  - Kari Stefansson
AU  - Mette Nyegaard
AU  - Anders D. Børglum
TI  - Genome-wide association study implicates <em>CHRNA2</em> in cannabis use disorder
AID  - 10.1101/237321
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 237321
4099  - http://biorxiv.org/content/early/2017/12/21/237321.short
4100  - http://biorxiv.org/content/early/2017/12/21/237321.full
AB  - Cannabis is among the most frequently used illicit psychoactive substance worldwide1. Life time use was 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) based on 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, indicating potential therapeutic use in CUD of compounds with agonistic effect on CHRNA2.At the polygenic level analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance.