| Literature DB >> 31209380 |
Ditte Demontis1,2,3, Veera Manikandan Rajagopal4,5,6, Thorgeir E Thorgeirsson7, Thomas D Als4,5,6, Jakob Grove4,5,6,8, Kalle Leppälä4,5,6, Daniel F Gudbjartsson7, Jonatan Pallesen4,5,6, Carsten Hjorthøj5,9, Gunnar W Reginsson7, Thorarinn Tyrfingsson10, Valgerdur Runarsdottir10, Per Qvist4,5,6, Jane Hvarregaard Christensen4,5,6, Jonas Bybjerg-Grauholm5,11, Marie Bækvad-Hansen5,11, Laura M Huckins12,13, Eli A Stahl12,13, Allan Timmermann14, Esben Agerbo5,14,15, David M Hougaard5,11, Thomas Werge5,16,17, Ole Mors5,18, Preben Bo Mortensen5,14,15, Merete Nordentoft5,9,19, Mark J Daly20,21,22, Hreinn Stefansson7, Kari Stefansson7, Mette Nyegaard4,5, Anders D Børglum23,24,25.
Abstract
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.Entities:
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Year: 2019 PMID： 31209380 DOI： 10.1038/s41593-019-0416-1
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 24.884