Schizophrenia Research 151 (2013) 289–290
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Age at onset of schizophrenia: Cannabis, COMT gene, and their interactions
Dear Editor, Debate remains regarding risk factors that modify the age at onset (AAO) of schizophrenia (SCZ) including: sex, genetics, and cannabis use. It is estimated that 14% of existing SCZ cases could have been prevented if cannabis use was avoided (Moore et al., 2007). Arseneault et al. (2004) found that cannabis use led to a two-fold increase in the risk for SCZ later in life. The relationship between cannabis use and genetics in SCZ is less clear in the literature, though some interactions have been found (Di Forti et al., 2012). There is still debate as to whether a link exists between cannabis use, the COMT Val158Met variant, and SCZ. Some studies support this claim (Caspi et al., 2005; Pelayo-Teran et al., 2010), while others do not (Kantrowitz et al., 2009; Zammit et al., 2011). We hypothesized that high cannabis use would lead to an earlier AAO of SCZ, and that this interaction would be influenced by COMT genotype, specifically with Met carriers of Val158Met variant having a later AAO. We retrospectively assessed 403 individuals of European ancestry with a DSM-IV diagnosis of SCZ or schizoaffective disorder-depressive type. Structured Clinical Interviews for the DSM-IV Axis 1 Disorders (SCID-I/P) were conducted by trained research staff. AAO of psychosis was measured as age of first hospitalization for psychotic symptoms, obtained from the SCID-I/P interview or medical records. Cannabis use was coded as a binary variable: low users (those who used cannabis less than once per month, or never used cannabis), and high users (those who met DSM-IV criteria for cannabis abuse or dependence). Cannabis use was assessed over a lifetime period, precluding our findings from exploring the effects of acute or sporadic usage. Exclusion criteria were: neurological disorders, injury resulting in the loss of consciousness, history of drug-induced psychosis, or a diagnosis of schizoaffective disorderbipolar type. Informed consent was obtained from participants with the approval of the Centre for Addiction and Mental Health's Research Ethics Board. Single nucleotide polymorphisms (SNPs) in the COMT gene (rs4680 Val158Met, rs4633, rs4818, and rs6269) were genotyped using TaqMan assays according to the manufacturer's protocol (Applied Biosystems Inc., Foster City, CA). Genotype calls were checked by two experienced researchers and N 10% of samples were re-genotyped to assess accuracy. All SNPs were in Hardy–Weinberg equilibrium and 100% genotyping concordance was observed. Mean differences were identified using independent sample t-tests or ANOVA analyses, and χ2 tests were used for categorical variables, unless otherwise stated. The COMT-SNP × cannabis use interactions on AAO were explored using ANCOVA analyses. Power calculations were done using QUANTO v1.2.4 (http://hydra.usc.edu/gxe/). In our sample of participants with complete cannabis and AAO data (n = 308), we have N80% power to detect the effect of cannabis (at 40% prevalence) explaining down to 2% of variance in AAO. In the COMT SNP analysis, assuming an additive model and a minor allele frequency of 30%, we 0920-9964/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.10.037
have N80% power to detect down to 3% variance in AAO. In the COMTSNP × cannabis use interaction analysis, we have N 80% power to detect as low as 3% of the variance in AAO. In the total sample males had a significantly earlier AAO than females, and high users of cannabis had an earlier AAO relative to low users (Table 1). In addition, high cannabis use was more prevalent in males compared to females (χ2 = 20.5; p b 0.001; n = 316; OR = 3.47, 2.0– 6.0). In the analysis stratified by gender we found that male high users had a significantly earlier AAO compared to male low users. The smaller sample of females showed the same direction of effect of cannabis on AAO, however, it was not statistically significant (Table 1). No significant main effect of any genotype or genotype x cannabis interaction on AAO was observed in the total sample, or in the sample stratified by sex. This study provides evidence that cannabis use modifies the AAO of SCZ. Males, known to have an earlier AAO than females, had an even earlier AAO if they were high users of cannabis. Our results suggest that there may be a sex specific interaction between cannabis use, and AAO of SCZ. No interaction between COMT genotypes and cannabis use was found. There were a number of limitations to this study. Perhaps most important of these is that this study was conducted retrospectively. Furthermore, our data on cannabis use is limited by recall bias and the length of time between the first cannabis use and the assessment of the participant. In addition we have no data on the tetrahydrocannabinol or cannabidiol content, known to be highly variable, of the many different sources of cannabis used by our large urban sample. Overall our findings continue to support the observations that cannabis use can lead to poorer outcomes in SCZ patients. These findings may have important implications for educating the public, and in particular, counseling young people regarding cannabis use (Arseneault et al., 2004; Meier et al., 2012).
Role of funding source Funding for this study was provided by: The Canadian Institutes of Health Research (JLK), The Brain and Behavior Research Foundation (NARSAD Award to AKT); The American Foundation for Suicide Prevention (Postdoctoral Fellowship Award to CCZ); Eli Lily, Canada (CCZ); The Ontario Ministry of Economic Development and Innovation (JLK); and the Campbell Family Mental Health Research Institute. The aforementioned agencies had no role in the implementation of this study, from design to publication.
Table 1 Age at onset of participants according to sex and cannabis usage. Variable Gender (n = 403) Cannabis usea
a
Males Females High users Low users Male high users Male low users Female high users Female low users
Sample size (%)
Mean AAO (standard deviation)
p-Value
291 (72.2) 112 (27.8) 185 (60.1) 123 (39.9) 111 (52.1) 102 (47.9) 74 (77.9) 21 (22.1)
20.3 (5.2) 22.5 (6.5) 19.8 (5.4) 21.8 (6.1) 19.5 (5.3) 21.0 (5.2) 21.6 (5.8) 23.0 (7.3)
0.005 0.003 0.020 0.441
Sufficient information was available for n = 308 participants; AAO: age at onset.
290
Letter to the Editor
Contributors Formulation of the problem and design of the experiments: JLK, KRD, AKT and BM. Genotyping and data analysis: KRD, CCZ and AKT. First draft of manuscript and literature review: KRD and DEG. Editing and revising of manuscript: all authors. All authors have contributed to and have approved the final manuscript. Conflict of interest The authors KRD/AKT/DEG/BM/CCZ report no conflicts of interest. JLK has been a consultant to Eli Lilly, Roche Pharma, and Dainippon-Sumitomo. Acknowledgment We thank Natalie Freeman and Andrea Smart for their administrative support, and Elaine Bennett for assisting with data compilation.
References Arseneault, L., Cannon, M., Witton, J., Murray, R.M., 2004. Causal association between cannabis and psychosis: examination of the evidence. Br. J. Psychiatry 184, 110–117. Caspi, A., Moffitt, T.E., Cannon, M., McClay, J., Murray, R., Harrington, H., et al., 2005. 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 × environment interaction. Biol. Psychiatry 57, 1117–1127. Di Forti, M., Iyegbe, C., Sallis, H., Kolliakou, A., Falcone, M.A., Paparelli, A., Sirianni, M., La Cascia, C., Stilo, S.A., Marques, T.R., Handley, R., Mondelli, V., Dazzan, P., Pariante, C., David, A.S., Morgan, C., Powell, J., Murray, R.M., 2012. Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users. Biol. Psychiatry 72 (10), 811–816. Kantrowitz, J.T., Nolan, K.A., Sen, S., Simen, A.A., Lachman, H.M., Bowers Jr., M.B., 2009. Adolescent cannabis use, psychosis and catechol-O-methyltransferase genotype in African Americans and Caucasians. Psychiatry Q. 80, 213–218. Meier, M.H., Caspi, A., Ambler, A., Harrington, H., Houts, R., Keefe, R.S., McDonald, K., Ward, A., Poulton, R., Moffitt, T.E., 2012. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc. Natl. Acad. Sci. U. S. A. 109 (40) E2657–E2664 (Oct 2).
Moore, T.H., Zammit, S., Lingford-Hughes, A., Barnes, T.R., Jones, P.B., Burke, M., Lewis, G., 2007. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370, 319–328. Pelayo-Teran, J.M., Perez-Iglesias, R., Mata, I., Carrasco-Marin, E., Vazquez-Barquero, J.L., Crespo-Facorro, B., 2010. Catechol-O-Methyltransferase (COMT) Val158Met variations and cannabis use in first-episode non-affective psychosis: clinical-onset implications. Psychiatry Res. 179, 291–296. Zammit, S., Owen, M.J., Evans, J., Heron, J., Lewis, G., 2011. Cannabis, COMT and psychotic experiences. Br. J. Psychiatry 199, 380–385.
Kim R. De Sousa Arun K. Tiwari Daniel E. Giuffra Bronwyn Mackenzie Clement C. Zai Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada James L. Kennedy Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Corresponding author at: Centre for Addiction and Mental Health, University of Toronto, 250 College St. Room 129, Toronto, ON M5T 1R8, Canada. Tel.: +1 416 535 8501x4987. E-mail address: [email protected]. 31 October 2012
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Age at onset of schizophrenia: Cannabis, COMT gene, and their interactions
Dear Editor, Debate remains regarding risk factors that modify the age at onset (AAO) of schizophrenia (SCZ) including: sex, genetics, and cannabis use. It is estimated that 14% of existing SCZ cases could have been prevented if cannabis use was avoided (Moore et al., 2007). Arseneault et al. (2004) found that cannabis use led to a two-fold increase in the risk for SCZ later in life. The relationship between cannabis use and genetics in SCZ is less clear in the literature, though some interactions have been found (Di Forti et al., 2012). There is still debate as to whether a link exists between cannabis use, the COMT Val158Met variant, and SCZ. Some studies support this claim (Caspi et al., 2005; Pelayo-Teran et al., 2010), while others do not (Kantrowitz et al., 2009; Zammit et al., 2011). We hypothesized that high cannabis use would lead to an earlier AAO of SCZ, and that this interaction would be influenced by COMT genotype, specifically with Met carriers of Val158Met variant having a later AAO. We retrospectively assessed 403 individuals of European ancestry with a DSM-IV diagnosis of SCZ or schizoaffective disorder-depressive type. Structured Clinical Interviews for the DSM-IV Axis 1 Disorders (SCID-I/P) were conducted by trained research staff. AAO of psychosis was measured as age of first hospitalization for psychotic symptoms, obtained from the SCID-I/P interview or medical records. Cannabis use was coded as a binary variable: low users (those who used cannabis less than once per month, or never used cannabis), and high users (those who met DSM-IV criteria for cannabis abuse or dependence). Cannabis use was assessed over a lifetime period, precluding our findings from exploring the effects of acute or sporadic usage. Exclusion criteria were: neurological disorders, injury resulting in the loss of consciousness, history of drug-induced psychosis, or a diagnosis of schizoaffective disorderbipolar type. Informed consent was obtained from participants with the approval of the Centre for Addiction and Mental Health's Research Ethics Board. Single nucleotide polymorphisms (SNPs) in the COMT gene (rs4680 Val158Met, rs4633, rs4818, and rs6269) were genotyped using TaqMan assays according to the manufacturer's protocol (Applied Biosystems Inc., Foster City, CA). Genotype calls were checked by two experienced researchers and N 10% of samples were re-genotyped to assess accuracy. All SNPs were in Hardy–Weinberg equilibrium and 100% genotyping concordance was observed. Mean differences were identified using independent sample t-tests or ANOVA analyses, and χ2 tests were used for categorical variables, unless otherwise stated. The COMT-SNP × cannabis use interactions on AAO were explored using ANCOVA analyses. Power calculations were done using QUANTO v1.2.4 (http://hydra.usc.edu/gxe/). In our sample of participants with complete cannabis and AAO data (n = 308), we have N80% power to detect the effect of cannabis (at 40% prevalence) explaining down to 2% of variance in AAO. In the COMT SNP analysis, assuming an additive model and a minor allele frequency of 30%, we 0920-9964/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.10.037
have N80% power to detect down to 3% variance in AAO. In the COMTSNP × cannabis use interaction analysis, we have N 80% power to detect as low as 3% of the variance in AAO. In the total sample males had a significantly earlier AAO than females, and high users of cannabis had an earlier AAO relative to low users (Table 1). In addition, high cannabis use was more prevalent in males compared to females (χ2 = 20.5; p b 0.001; n = 316; OR = 3.47, 2.0– 6.0). In the analysis stratified by gender we found that male high users had a significantly earlier AAO compared to male low users. The smaller sample of females showed the same direction of effect of cannabis on AAO, however, it was not statistically significant (Table 1). No significant main effect of any genotype or genotype x cannabis interaction on AAO was observed in the total sample, or in the sample stratified by sex. This study provides evidence that cannabis use modifies the AAO of SCZ. Males, known to have an earlier AAO than females, had an even earlier AAO if they were high users of cannabis. Our results suggest that there may be a sex specific interaction between cannabis use, and AAO of SCZ. No interaction between COMT genotypes and cannabis use was found. There were a number of limitations to this study. Perhaps most important of these is that this study was conducted retrospectively. Furthermore, our data on cannabis use is limited by recall bias and the length of time between the first cannabis use and the assessment of the participant. In addition we have no data on the tetrahydrocannabinol or cannabidiol content, known to be highly variable, of the many different sources of cannabis used by our large urban sample. Overall our findings continue to support the observations that cannabis use can lead to poorer outcomes in SCZ patients. These findings may have important implications for educating the public, and in particular, counseling young people regarding cannabis use (Arseneault et al., 2004; Meier et al., 2012).
Role of funding source Funding for this study was provided by: The Canadian Institutes of Health Research (JLK), The Brain and Behavior Research Foundation (NARSAD Award to AKT); The American Foundation for Suicide Prevention (Postdoctoral Fellowship Award to CCZ); Eli Lily, Canada (CCZ); The Ontario Ministry of Economic Development and Innovation (JLK); and the Campbell Family Mental Health Research Institute. The aforementioned agencies had no role in the implementation of this study, from design to publication.
Table 1 Age at onset of participants according to sex and cannabis usage. Variable Gender (n = 403) Cannabis usea
a
Males Females High users Low users Male high users Male low users Female high users Female low users
Sample size (%)
Mean AAO (standard deviation)
p-Value
291 (72.2) 112 (27.8) 185 (60.1) 123 (39.9) 111 (52.1) 102 (47.9) 74 (77.9) 21 (22.1)
20.3 (5.2) 22.5 (6.5) 19.8 (5.4) 21.8 (6.1) 19.5 (5.3) 21.0 (5.2) 21.6 (5.8) 23.0 (7.3)
0.005 0.003 0.020 0.441
Sufficient information was available for n = 308 participants; AAO: age at onset.
290
Letter to the Editor
Contributors Formulation of the problem and design of the experiments: JLK, KRD, AKT and BM. Genotyping and data analysis: KRD, CCZ and AKT. First draft of manuscript and literature review: KRD and DEG. Editing and revising of manuscript: all authors. All authors have contributed to and have approved the final manuscript. Conflict of interest The authors KRD/AKT/DEG/BM/CCZ report no conflicts of interest. JLK has been a consultant to Eli Lilly, Roche Pharma, and Dainippon-Sumitomo. Acknowledgment We thank Natalie Freeman and Andrea Smart for their administrative support, and Elaine Bennett for assisting with data compilation.
References Arseneault, L., Cannon, M., Witton, J., Murray, R.M., 2004. Causal association between cannabis and psychosis: examination of the evidence. Br. J. Psychiatry 184, 110–117. Caspi, A., Moffitt, T.E., Cannon, M., McClay, J., Murray, R., Harrington, H., et al., 2005. 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 × environment interaction. Biol. Psychiatry 57, 1117–1127. Di Forti, M., Iyegbe, C., Sallis, H., Kolliakou, A., Falcone, M.A., Paparelli, A., Sirianni, M., La Cascia, C., Stilo, S.A., Marques, T.R., Handley, R., Mondelli, V., Dazzan, P., Pariante, C., David, A.S., Morgan, C., Powell, J., Murray, R.M., 2012. Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users. Biol. Psychiatry 72 (10), 811–816. Kantrowitz, J.T., Nolan, K.A., Sen, S., Simen, A.A., Lachman, H.M., Bowers Jr., M.B., 2009. Adolescent cannabis use, psychosis and catechol-O-methyltransferase genotype in African Americans and Caucasians. Psychiatry Q. 80, 213–218. Meier, M.H., Caspi, A., Ambler, A., Harrington, H., Houts, R., Keefe, R.S., McDonald, K., Ward, A., Poulton, R., Moffitt, T.E., 2012. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc. Natl. Acad. Sci. U. S. A. 109 (40) E2657–E2664 (Oct 2).
Moore, T.H., Zammit, S., Lingford-Hughes, A., Barnes, T.R., Jones, P.B., Burke, M., Lewis, G., 2007. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370, 319–328. Pelayo-Teran, J.M., Perez-Iglesias, R., Mata, I., Carrasco-Marin, E., Vazquez-Barquero, J.L., Crespo-Facorro, B., 2010. Catechol-O-Methyltransferase (COMT) Val158Met variations and cannabis use in first-episode non-affective psychosis: clinical-onset implications. Psychiatry Res. 179, 291–296. Zammit, S., Owen, M.J., Evans, J., Heron, J., Lewis, G., 2011. Cannabis, COMT and psychotic experiences. Br. J. Psychiatry 199, 380–385.
Kim R. De Sousa Arun K. Tiwari Daniel E. Giuffra Bronwyn Mackenzie Clement C. Zai Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada James L. Kennedy Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Corresponding author at: Centre for Addiction and Mental Health, University of Toronto, 250 College St. Room 129, Toronto, ON M5T 1R8, Canada. Tel.: +1 416 535 8501x4987. E-mail address: [email protected]. 31 October 2012
