Advertisement

Confirmation that the AKT1 (rs2494732) Genotype Influences the Risk of Psychosis in Cannabis Users

      Background

      Cannabis use is associated with an increased risk of psychosis. One study has suggested that genetic variation in the AKT1 gene might influence this effect.

      Methods

      In a case-control study of 489 first-episode psychosis patients and 278 control subjects, we investigated the interaction between variation at the AKT1 rs2494732 single nucleotide polymorphism and cannabis use in increasing the risk of psychosis.

      Results

      The rs2494732 locus was not associated with an increased risk of a psychotic disorder, with lifetime cannabis use, or with frequency of use. We did, however, find that the effect of lifetime cannabis use on risk of psychosis was significantly influenced by the rs2494732 locus (likelihood ratio statistic for the interaction = 8.54; p = .014). Carriers of the C/C genotype with a history of cannabis use showed a greater than twofold increased likelihood of a psychotic disorder (odds ratio = 2.18 [95% confidence interval: 1.12, 4.31]) when compared with users who were T/T carriers. Moreover, the interaction between the rs2494732 genotype and frequency of use was also significant at the 5% level (likelihood ratio = 13.39; p = .010). Among daily users, C/C carriers demonstrated a sevenfold increase in the odds of psychosis compared with T/T carriers (odds ratio = 7.23 [95% confidence interval: 1.37, 38.12]).

      Conclusions

      Our findings provide strong support for the initial report that genetic variation at rs2494732 of AKT1 influences the risk of developing a psychotic disorder in cannabis users.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • United Nations Office on Drugs and Crime
        UNODC World Drug Report 2009.
        2009
        • Henquet C.
        • Murray R.
        • Linszen D.
        • van Os J.
        The environment and schizophrenia: The role of cannabis use.
        Schizophr Bull. 2005; 31: 608-612
        • Moore T.H.
        • Zammit S.
        • Lingford-Hughes A.
        • Barnes T.R.
        • Jones P.B.
        • Burke M.
        • Lewis G.
        Cannabis use and risk of psychotic or affective mental health outcomes: A systematic review.
        Lancet. 2007; 370: 319-328
        • Caspi A.
        • Moffitt T.E.
        • Cannon M.
        • McClay J.
        • Murray R.
        • Harrington H.
        • et al.
        Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: Longitudinal evidence of a gene x environment interaction.
        Biol Psychiatry. 2005; 57: 1117-1127
        • Henquet C.
        • Rosa A.
        • Krabbendam L.
        • Papiol S.
        • Fananas L.
        • Drukker M.
        • et al.
        An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition.
        Neuropsychopharmacology. 2006; 31: 2748-2757
        • Thiselton D.L.
        • Vladimirov V.I.
        • Kuo P.H.
        • McClay J.
        • Wormley B.
        • Fanous A.
        • et al.
        AKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish study of high density schizophrenia families.
        Biol Psychiatry. 2008; 63: 449-457
        • Karege F.
        • Meary A.
        • Perroud N.
        • Jamain S.
        • Leboyer M.
        • Ballmann E.
        • et al.
        Genetic overlap between schizophrenia and bipolar disorder: A study with AKT1 gene variants and clinical phenotypes.
        Schizophr Res. 2012; 135: 8-14
        • Bolog Z.
        • Kiss I.
        • Bolcs K.M.
        New schizophrenia loci may converge on the same cellular mechanism: The AKT pathway.
        Am J Psychiatry. 2012; 169: 3
        • Bozzi Y.
        • Dunleavy M.
        • Henshall D.C.
        Cell signaling underlying epileptic behavior.
        Front Behav Neurosci. 2011; 5: 45
        • Ozaita A.
        • Puighermanal E.
        • Maldonado R.
        Regulation of PI3K/Akt/GSK-3 pathway by cannabinoids in the brain.
        J Neurochem. 2007; 102: 1105-1114
        • Gomez del Pulgar T.
        • Velasco G.
        • Guzman M.
        The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt.
        Biochem J. 2000; 347: 369-373
        • van Winkel R.
        Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: Sibling analysis and proband follow-up.
        Arch Gen Psychiatry. 2011; 68: 148-157
        • van Winkel R.
        • van Beveren N.J.
        • Simons C.
        • Genetic Risk and Outcome of Psychosis (GROUP) Investigators
        AKT1 moderation of cannabis-induced cognitive alterations in psychotic disorder.
        Neuropsychopharmacology. 2011; 36: 2529-2537
        • Bhattacharyya S.
        • Atakan Z.
        • Martin-Santos R.
        • Crippa J.A.
        • Kambeitz J.
        • Prata D.
        • et al.
        Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of d-9-tetrahydrocannabinol on midbrain and striatal function [published online ahead of print January 31].
        Mol Psychiatry. 2012;
        • Duncan L.E.
        • Keller M.C.
        A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry.
        Am J Psychiatry. 2011; 168: 1041-1049
        • World Health Organization
        International Classification of Diseases, 10th Edition (ICD-10): Classification of Mental and Behavioural Disorders.
        World Health Organization, Geneva1992
        • World Health Organization
        Schedules for Clinical Assessment in Neuropsychiatry (SCAN).
        World Health Organization, Geneva1992
        • Office for National Statistics
        2011 Census.
        • Bebbington P.
        • Nayani T.
        The Psychosis Screening Questionnaire.
        Int J Methods Psychiatr Res. 1995; 5: 11-19
        • Mallett R.
        • Leff J.
        • Bhugra D.
        • Pang D.
        • Zhao J.H.
        Social environment, ethnicity and schizophrenia.
        Soc Psychiatry Psychiatr Epidemiol. 2002; 37: 329-335
        • Di Forti M.
        • Morgan C.
        • Dazzan P.
        • Pariante C.
        • Mondelli V.
        • Marques T.R.
        • et al.
        High-potency cannabis and the risk of psychosis.
        Br J Psychiatry. 2009; 195: 488-491
        • Falush D.
        • Stephens M.
        • Pritchard J.K.
        Inference of population structure using multilocus genotype data: Linked loci and correlated allele frequencies.
        Genetics. 2003; 164: 1567-1587
        • Morrison P.D.
        • Murray R.M.
        From real-world events to psychosis: The emerging neuropharmacology of delusions.
        Schizophr Bull. 2009; 35: 668-674
        • Adermark L.
        • Talani G.
        • Lovinger D.M.
        Endocannabinoid-dependent plasticity at GABAergic and glutamatergic synapses in the striatum is regulated by synaptic activity.
        Eur J Neurosci. 2009; 29: 32-41
        • Laruelle M.
        • Abi-Dargham A.
        Dopamine as the wind of the psychotic fire: New evidence from brain imaging studies.
        J Psychopharmacol. 1999; 13: 358-371
        • Abi-Dargham A.
        • Rodenhiser J.
        • Printz D.
        • Zea-Ponce Y.
        • Gil R.
        • Kegeles L.S.
        • et al.
        Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.
        Proc Natl Acad Sci U S A. 2000; 97: 8104-8109
        • Zammit S.
        • Spurlock G.
        • Williams H.
        • Norton N.
        • Williams N.
        • O'Donovan M.C.
        • Owen M.J.
        Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: Interactions with tobacco and cannabis use.
        Br J Psychiatry. 2007; 191: 402-407
        • Cross D.A.
        • Alessi D.R.
        • Cohen P.
        • Andjelkovich M.
        • Hemmings B.A.
        Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.
        Nature. 1995; 378: 785-789
        • Scheid M.P.
        • Woodgett J.R.
        PKB/AKT: Functional insights from genetic models.
        Nat Rev Mol Cell Biol. 2011; 2: 760-768
        • Blasi G.
        • Napolitano F.
        • Ursinia G.
        • Taurisano P.
        • Romanoa R.
        • Caforio G.
        • et al.
        DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia.
        Proc Natl Acad Sci U S A. 2011; 108: 1158-1163
        • Sanchez M.G.
        • Ruiz-Llorente L.
        • Sanchez A.M.
        • Diaz-Laviada I.
        Activation of phosphoinositide 3-kinase/PKB pathway by CB(1) and CB(2) cannabinoid receptors expressed in prostate PC-3 cells.
        Cell Signal. 2003; 15: 851-859
        • Beaulieu J.M.
        • Gainetdinov R.R.
        • Caron M.G.
        The Akt-GSK-3 signaling cascade in the actions of dopamine.
        Trends Pharmacol Sci. 2007; 28: 166-172
        • Beaulieu J.M.
        • Tirotta E.
        • Sotnikova T.D.
        • Masri B.
        • Salahpour A.
        • Gainetdinov R.R.
        • et al.
        Regulation of Akt signaling by D2 and D3 dopamine receptors in vivo.
        J Neurosci. 2007; 27: 881-885
        • British Crime Survey
        Crime Surveys Programme Research Development and Statistics Crime Reduction and Community Safety Group Home Office.
        2007/2008
        • National Center for Biotechnology Information
        dbSNP Short Genetic Variations.
        (Accessed February 2012)
        • Altshuler D.M.
        • Gibbs R.A.
        • Peltonen L.
        • Altshuler D.M.
        • Gibbs R.A.
        • et al.
        • The International HapMap 3 Consortium
        Integrating common and rare genetic variation in diverse human populations.
        Nature. 2012; 467: 52-58
        • Tan H.-Y.
        • Nicodemus K.K.
        • Chen Q.
        • Li Z.
        • Brooke J.K.
        • Honea R.
        • et al.
        Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans.
        J Clin Invest. 2008; 118: 2200-2208
        • Khoury M.J.
        • Flanders W.D.
        Non traditional epidemiologic approaches in the analysis of gene-environment interaction: Case-control studies with no controls!.
        Am J Epidemiol. 1996; 144: 207-213
        • Moffitt T.E.
        • Caspi A.
        • Rutter M.
        Strategy for investigating interactions between measured genes and measured environments.
        Arch Gen Psychiatry. 2005; 62: 473-481
        • Purcell S.M.
        • Wray N.R.
        • Stone J.L.
        • Visscher P.M.
        • O'Donovan M.C.
        • et al.
        • International Schizophrenia Consortium
        Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.
        Nature. 2009; 460: 748-752