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Confirmation That the AKT1 (Rs2494732) Genotype Influences the Risk of Psychosis in Cannabis Users

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Confirmation That the AKT1 (Rs2494732) Genotype Influences the Risk of Psychosis in Cannabis Users PRIORITY COMMUNICATION Confirmation that the AKT1 (rs2494732) Genotype Influences the Risk of Psychosis in Cannabis Users Marta Di Forti, Conrad Iyegbe, Hannah Sallis, Anna Kolliakou, M. Aurora Falcone, Alessandra Paparelli, Miriam Sirianni, Caterina La Cascia, Simona A. Stilo, Tiago Reis Marques, Rowena Handley, Valeria Mondelli, Paola Dazzan, Carmine Pariante, Anthony S. David, Craig Morgan, John Powell, and Robin M. Murray 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 ϭ 8.54; p ϭ .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 ϭ 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 ϭ 13.39; p ϭ .010). Among daily users, C/C carriers demonstrated a sevenfold increase in the odds of psychosis compared with T/T carriers (odds ratio ϭ 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: AKT1 gene, cannabis use, gene ϫ environment inter- van Winkel et al. (12) studied 801 patients with schizophrenia and action, psychosis, schizophrenia, signaling pathways 740 of their siblings and reported that subjects who carried two copies of the C allele of the rs2494732 polymorphism of the AKT1 annabis is the most commonly used illicit drug in the world gene were especially at risk of schizophrenia and schizotypy, re- (1). Most people who use it come to no harm. However, it has spectively, if they used cannabis. In a separate study, van Winkel et become apparent in recent years that cannabis use is a risk al. (13) also reported an AKT1-cannabis interaction on cognitive C performance. Among psychotic patients who used cannabis, carri- factor for the development of schizophrenia-like psychotic disor- ders (2,3). Why certain individuals develop psychosis when their ers of the AKT1 rs2494732 C/C genotype did significantly worse on a peers, who smoke similar amounts of cannabis, remain well is un- test of sustained attention compared with T/T carriers (13). More- clear. One suggestion is that such individuals may carry some ge- over, a neuroimaging study showed that healthy subjects carrying netic susceptibility (4,5). Should the genes underlying such suscep- the dopamine transporter 9-repeat and the AKT1 rs130233 G/G tibility be identified, this would be of considerable public health genotype had the greatest psychotic response and striatal activa- tion following administration of delta-9-THC (14). importance. ϫ ϫ One candidate for a gene ϫ cannabis interaction is the AKT1 A recent critical review of gene environment (G E) research gene, which has been associated with schizophrenia in some but in psychiatry concluded that direct replications deserve more at- tention than novel findings or indirect replications (15). We there- not all studies (6–8). The AKT1 gene is an attractive candidate ϫ because it codes for a protein kinase that forms an integral part of fore set out to directly test the veracity of the AKT1 rs2494732 the dopamine receptor signaling cascade in the striatum (9). More- cannabis interaction in a sample of patients with their first episode over, in vivo administration to mice of delta-9-tetrahydrocannabi- of psychosis and healthy control subjects in south London. Because nol (delta-9-TCH), the active ingredient in cannabis, activates this of this a priori hypothesis, rs2494732 was the only locus genotyped signaling cascade via AKT1 phosphorylation (10,11). Furthermore, and tested for interaction with cannabis use. From the Departments of Psychosis Studies (MDF, AK, MAF, TRM, PD, ASD, Methods and Materials RMM); Neuroscience (CI, AP, JP); and Biostatistics (HS), Institute of Psy- Participants chiatry, Kings College London, London, United Kingdom; Department of Participants were part of the Genetic and Psychotic Disorders Psychiatry (MS), Catanzaro Medical School, Catanzaro; and Department of Psychiatry and Neuroscience (CLC), Palermo University, Palermo, Italy; Study case-control project that approached all patients aged 18 to and Departments of Health Services and Public Health (SAS, RH, CM) and 65 years who presented with their first episode of psychosis to the Psychological Medicine (VM, CP), Institute of Psychiatry, Kings College Lambeth, Southwark, and Croydon adult inpatient units of the London, London, United Kingdom. South London and Maudsley National Health Service Foundation Address correspondence to Marta Di Forti, M.D., Ph.D., Kings College Lon- Trust between December 2005 and October 2010. Patients who don, Department of Psychosis Studies, Institute of Psychiatry, De Cre- met ICD-10 criteria for a diagnosis of nonorganic psychosis (F20– spigny Park, London SE5 8AF, United Kingdom; E-mail: marta.diforti@ F29 and F30–F33) (16), validated by administering the Schedules kcl.ac.uk. for Clinical Assessment in Neuropsychiatry (17), were invited to Received Mar 29, 2012; revised Jun 5, 2012; accepted Jun 6, 2012. participate in the study. Of the total approached (734), 20% (145) 0006-3223/$36.00 BIOL PSYCHIATRY 2012;xx:xxx http://dx.doi.org/10.1016/j.biopsych.2012.06.020 © 2012 Society of Biological Psychiatry 2 BIOL PSYCHIATRY 2012;xx:xxx M. Di Forti et al. refused to participate and 596 patients experiencing their first epi- mation on the makeup of the marker panel is available on request. sode of psychosis were successfully recruited into the study. The Ancestry scores were derived using the program Structure (22)to two most common reasons for refusal were a lack of interest in the implement a model-based (Markov Chain Monte Carlo) clustering research and the length of the full assessment. algorithm. Having determined the best solution for K (the probable Over the same time frame, from the area served by the same true number of underlying genetic groups) in initial analyses, indi- mental health units, we recruited a sample of 333 healthy control viduals who scored between 96% and 100% for genetic cluster subjects, aged 18 to 65 years, which was broadly similar to the local membership were used to create a three-way ancestral axis based population in terms of ethnicity, educational attainment, and em- on Black African (n ϭ 81), European Caucasian (n ϭ 118), and Asian ployment status (18), using internet and newspaper advertise- (n ϭ 16) ancestry. These reference groups were used to index ge- ments and distribution of leaflets at train stations, shops, and job netic ancestry for the remaining sample (Figure 1). Eighty-three centers. None of the material used for advertising mentioned can- percent of participants had information on both self-reported eth- nabis or illicit drug use. Volunteers willing to take part in the study nicity and ancestry markers. Using 95% to define the cutoff point for were administered the Psychosis Screening Questionnaire (19) and cluster membership resulted in the genetic validation of 241 self- were excluded if they met criteria for a psychotic disorder or if they reported ethnicities. The level of overall agreement between self- reported a previous diagnosis of psychotic illness. reported and genetic ethnicities (96%) was reassuringly high. Further details on the age distribution of the samples and on the diagnostic breakdown of the cases are available in Tables S1 and S2 Ethics in Supplement 1. This study was part of the GAP study, which was granted ethical The data presented in this study are based on the 489 first- approval by the South London and Maudsley and Institute of Psy- episode psychosis patients (82% of the total recruited) and 278 chiatry Local Research Ethics Committee. All cases and control sub- control subjects (83% of the total recruited) on whom we were able jects included in the study gave informed written consent, signing to obtain both a history concerning cannabis use and DNA samples. the consent document, to the publication of data originating from the study. General Assessment and Data on Exposure of Interest Sociodemographic data (age, gender, self-reported ethnicity, level of education attainment, and employment status) on cases Data Analysis and control subjects were collected using the Medical Research Data were recorded in SPSS version 15 and analyzed using Stata Council Social Scale (20). Participants were asked if they had ever 11 (Stata, College Station, Texas). Based on the existing literature, a smoked tobacco, and if they drank alcohol, their weekly alcohol unit history of 1) ever having used cannabis (referred to hereafter as consumption was recorded. A detailed history of illicit drug use lifetime cannabis use) and 2) lifetime frequency of use were the (cannabis, stimulants, and any other recreational drug) was taken main environmental measures of interest. These were analyzed in using the Cannabis Experience Questionnaire modified version conjunction with rs2494732. Genotypes at this locus were coded (21). The two measures of exposure to cannabis use included in the (for initial tests of main effects) to reflect the allele dosage of the analyses were: 1) lifetime history of cannabis use, i.e., had the sub- SNP of interest selected in accordance with the original report (12): ϭ ϭ ϭ ject ever used cannabis at any point in the lifetime (No ϭ 0; Yes ϭ 1); T/T 0; C/T 1; C/C 2.
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