Genome-wide association study implicates CHRNA2 in cannabis use disorder
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Genome-wide association study implicates CHRNA2 in cannabis use disorder. / Demontis, Ditte; Rajagopal, Veera Manikandan; Thorgeirsson, Thorgeir E; Als, Thomas D; Grove, Jakob; Leppälä, Kalle; Gudbjartsson, Daniel F; Pallesen, Jonatan; Hjorthøj, Carsten; Reginsson, Gunnar W; Tyrfingsson, Thorarinn; Runarsdottir, Valgerdur; Qvist, Per; Christensen, Jane Hvarregaard; Bybjerg-Grauholm, Jonas; Bækvad-Hansen, Marie; Huckins, Laura M; Stahl, Eli A; Timmermann, Allan; Agerbo, Esben; Hougaard, David M; Werge, Thomas; Mors, Ole; Mortensen, Preben Bo; Nordentoft, Merete; Daly, Mark J; Stefansson, Hreinn; Stefansson, Kari; Nyegaard, Mette; Børglum, Anders D.
I: Nature Neuroscience, Bind 22, Nr. 7, 2019, s. 1066-1074.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Genome-wide association study implicates CHRNA2 in cannabis use disorder
AU - Demontis, Ditte
AU - Rajagopal, Veera Manikandan
AU - Thorgeirsson, Thorgeir E
AU - Als, Thomas D
AU - Grove, Jakob
AU - Leppälä, Kalle
AU - Gudbjartsson, Daniel F
AU - Pallesen, Jonatan
AU - Hjorthøj, Carsten
AU - Reginsson, Gunnar W
AU - Tyrfingsson, Thorarinn
AU - Runarsdottir, Valgerdur
AU - Qvist, Per
AU - Christensen, Jane Hvarregaard
AU - Bybjerg-Grauholm, Jonas
AU - Bækvad-Hansen, Marie
AU - Huckins, Laura M
AU - Stahl, Eli A
AU - Timmermann, Allan
AU - Agerbo, Esben
AU - Hougaard, David M
AU - Werge, Thomas
AU - Mors, Ole
AU - Mortensen, Preben Bo
AU - Nordentoft, Merete
AU - Daly, Mark J
AU - Stefansson, Hreinn
AU - Stefansson, Kari
AU - Nyegaard, Mette
AU - Børglum, Anders D
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
U2 - 10.1038/s41593-019-0416-1
DO - 10.1038/s41593-019-0416-1
M3 - Journal article
C2 - 31209380
VL - 22
SP - 1066
EP - 1074
JO - Nature Neuroscience
JF - Nature Neuroscience
SN - 1097-6256
IS - 7
ER -
ID: 224337777