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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.
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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Abuso de Maconha / Receptores Nicotínicos / Proteínas do Tecido Nervoso Tipo de estudo: Estudo de casos e controles / Estudo de coorte Aspecto clínico: Etiologia Limite: Feminino / Humanos / Masculino País/Região como assunto: Europa Idioma: Inglês Revista: Nat Neurosci Assunto da revista: Neurologia Ano de publicação: 2019 Tipo de documento: Artigo País de afiliação: Dinamarca