Genome-wide association study implicates CHRNA2 in cannabis use disorder.
Ditte DemontisVeera Manikandan RajagopalThorgeir E ThorgeirssonThomas Damm AlsJakob GroveKalle LeppäläDaníel F GuðbjartssonJonatan PallesenCarsten Rygaard HjorthøjGunnar W ReginssonThorarinn TyrfingssonValgerdur RunarsdottirPer QvistJane Hvarregaard ChristensenJonas Byberg-GrauholmMarie Bækvad-HansenLaura M HuckinsEli A StahlAllan TimmermannEsben AgerboDavid Michael HougaardThomas M WergeOle MorsPreben Bo MortensenMerete NordentoftMark J DalyHreinn StefánssonKári StefánssonMette NyegaardAnders Dupont BørglumPublished in: Nature neuroscience (2019)
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.