Genome-wide association study implicates CHRNA2 in cannabis use disorder

Demontis, D.; Rajagopal, V. M.; Thorgeirsson, T.; Als, T. D.; Grove, J.; Pallesen, J.; Hjorthoj, C.; Reginsson, G. W.; Tyrfingsson, T.; Runarsdottir, V.; Qvist, P.; Christensen, J. H.; Huckins, L. M.; Stahl, E. A.; Timmermann, A.; Agerbo, E.; Werge, T.; Mors, O.; Mortensen, P. B.; Nordentoft, M.; Daly, M.; Stefansson, H.; Stefansson, K.; Nyegaard, M.; Borglum, A. D.

doi:10.1101/237321

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bioRxiv · 10.1101/237321

Genome-wide association study implicates CHRNA2 in cannabis use disorder

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Abstract

Introductory paragraphCannabis 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=9.31x10-12) that replicates in an independent population (Preplication=3.27x10-3, Pmetaanalysis=9.09x10-12). 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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Demontis, D., Rajagopal, V. M., Thorgeirsson, T., Als, T. D., Grove, J., Pallesen, J., Hjorthoj, C., Reginsson, G. W., Tyrfingsson, T., Runarsdottir, V., Qvist, P., Christensen, J. H., Huckins, L. M., Stahl, E. A., Timmermann, A., Agerbo, E., Werge, T., Mors, O., Mortensen, P. B., Nordentoft, M., Daly, M., Stefansson, H., Stefansson, K., Nyegaard, M., Borglum, A. D.. 2017-12-21. Genome-wide association study implicates CHRNA2 in cannabis use disorder. https://doi.org/10.1101/237321

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