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Genetic variation of GRIN1 confers vulnerability to methamphetamine-dependent psychosis in a Thai population
Neuroscience Letters 551 (2013) 58–61
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Genetic variation of GRIN1 confers vulnerability to methamphetamine-dependent psychosis in a Thai population Rachanee Chanasong a , Samur Thanoi a,b , Paritat Watiktinkorn c , Gavin P. Reynolds d , Sutisa Nudmamud-Thanoi a,b,∗ a
Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand Centre of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand c Synphaet Hospital, Bangkok, Thailand d Biomedical Research Centre, Sheffield Hallam University, Sheffield, UK b
h i g h l i g h t s • • • •
A cohort of male METH dependence with psychosis was genotyped for two SNPs in GRIN1. G2108A SNP showed a very strong association with METH-induced psychosis. These results identify a potential risk factor for drug-induced psychosis. Genetic variation in glutamate system plays a role in the emergence of psychosis.
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Article history: Received 28 May 2013 Received in revised form 5 July 2013 Accepted 9 July 2013 Keywords: Pharmacogenetics GRIN1 Methamphetamine Psychosis Substance misuse
a b s t r a c t GRIN1 is a gene that encodes the N-methyl-d aspartate (NMDA) receptor subunit1 (NR1). Variations of GRIN1 have been identified as a risk factor for schizophrenia and drug dependence, supporting hypotheses of glutamatergic dysfunction in these disorders. Methamphetamine (METH) is a psychostimulant drug which can induce psychotic symptoms reminiscent of those found in schizophrenia; thus GRIN1 is a candidate gene for vulnerability to METH dependence or METH-dependent psychosis. The present study examined two polymorphisms of GRIN1, rs11146020 (G1001C) and rs1126442 (G2108A), in 100 male Thai METH-dependent patients and 103 healthy controls using PCR-RFLP techniques. Neither polymorphism was significantly associated with METH dependence, although rs1126442 was highly significantly associated with METH-dependent psychosis, in which the A allele showed reduced frequency (P < 0.00001). The present findings indicate that the rs1126442 of GRIN1 contributes to the genetic vulnerability to psychosis in METH-dependent subjects in the Thai population. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The fundamental pathophysiology of drug dependence is thought to involve dysfunction of the mesolimbic dopamine system underlying reward mechanisms [19,20,37,39]. However, increasing evidence indicates a role for the glutamatergic system, and particularly the NMDA receptor, in drug addiction [10,11,33,36]. Methamphetamine (METH) is a derivative of amphetamine which is classified as one of the psychostimulant group of addictive drugs. METH can induce psychotic symptoms which closely resemble schizophrenia [2,35]. In addition, METH administration
∗ Corresponding author at: Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand. Tel.: +66 55 964 672; fax: +66 55 964 770. E-mail address: [email protected] (S. Nudmamud-Thanoi). 0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.07.017
can induce behavioural sensitization which has been useful as an animal model of schizophrenia [5,17]. Certainly, there is substantial evidence implicating a dysfunction of glutamatergic neurotransmission in schizophrenia [21,22,24,32]. Therefore, METH dependence, or particularly the psychosis associated with METH dependence, may share some common underlying glutamatergic neuropathology with schizophrenia. N-methyl-d aspartate (NMDA) receptors are ionotropic glutamate receptors that play important roles in neurodevelopment and learning and memory [9,26]. In humans, the NR1 receptor subunit is translated from the GRIN1 gene which is located on chromosome 9q34.3 and is composed of 21 exons. It is required as a key receptor subunit for physiological function combined with one or more of the four NR2 subunits NMDAR2A–D to make the heterodimeric receptor complex [8,15,18,30]. Numerous studies have indicated a dysfunction of NR1 in both schizophrenia and drug
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abuse, particularly METH dependence. In METH-sensitized rats, it was found that NR1, NR2A, and NR2B proteins in the striatum were decreased [40]. Similarly, amphetamine exposure for 5 days and after 14 days of withdrawal exhibited decreased NR1 mRNA and protein in the nucleus accumbens but with increases in prefrontal cortex [16]. Following acute METH treatment, decreased expression of NR1 was found in the frontal cortex while NR2A was increased [31]. Additionally, in other studies where METH was given as either acute or subacute administration, an elevation of NR1 immunoreactivity (IR) was found in the striatum, whereas increased NR1-IR in the frontal cortex was only found in the subacute group [11]. A further approach to understanding how glutamate mechanisms contribute to drug dependence is its association with genetic variation; i.e. how single nucleotide polymorphisms (SNPs) in genes involved in glutamatergic function may contribute to individual differences in vulnerability to drug dependence. In alcohol studies, alcohol-associated anxiolysis and motor impairment were reduced in NR1 mutant mice by a reduction of glycine binding sites [12]. Interestingly, association studies in German alcoholics found the A allele of the G2108A SNP (rs1126442) in exon 7 of the NR1 gene (GRIN1) was more common in patients than in controls [27,38]. Furthermore, there are several studies in which SNPs of NMDA receptor genes were reported to be associated with elevated risk in schizophrenia. An increased frequency of the C allele of rs11146020 is reported in schizophrenia in various ethnicities [3,6,41]. This observation was found to be particularly in a subgroup with a lifetime history of depressive symptoms [7]. Additionally, this SNP has revealed an interaction with SNPs in the NR2B gene (GRIN2B), T4197C and T5988C, to confer vulnerability to the disease [25], and a meta-analysis also concluded that the C allele of rs11146020 may be a marker for a high risk for developing schizophrenia [28]. Taken together, this evidence suggests that genetic variation of GRIN1 provides a good candidate for association with METH dependence and its resultant psychosis. We have chosen to test these hypotheses in a Thai population in which METH abuse and dependence is a major social and medical concern. The present study therefore hypothesized that the genetic variation in two SNPs of GRIN1, rs11146020 (G1001C) and rs1126442 (G2108A), may confer susceptibility to METH dependence and METH psychosis in the Thai population.
2. Materials and methods 2.1. Subjects Subjects comprised 100 Thai METH dependent patients recruited from the Central Correctional Institution for Drug Addicts, Bangkok, Thailand, meeting criteria for METH dependence according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria [1]. Subjects were divided into those with or without a history of psychotic symptoms considered to be due to METH use. Psychiatric symptoms were treated according to local practice with antipsychotic, antidepressant or anxiolytic drugs as appropriate. 103 Thai control subjects were recruited, excluding those with a history of drug misuse or psychiatric disorder. Subjects were all male and age-matched (mean age ± SD 29.45 ± 4.55, range 21–45 years in patients, and 28.75 ± 6.39, range 20–46 years in controls). The average age of onset of METH use in patients was 19.52 ± 6.53, range 12–41 years, and the duration of METH use was 9.35 ± 5.26, range 1–23 years. All participants were informed with a complete and extensive explanation of the study, and signed consent forms approved by the Ethical Committees of Naresuan University, Thailand.
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2.2. SNP genotyping Blood samples from both patients and controls were obtained by fingertip venipuncture and were collected on FTA® cards (Whatman, WB120305, USA). The cards were washed with FTA purification reagent (Whatman, WB1202045, USA) until clear to obtain genomic DNA. PCR primers specific to rs11146020 (G1001C) in the 5 UTR region and rs1126442 (G2108A) in exon 7 of GRIN1 were designed based on the sequence and information from dbSNP database http://www.ncbi.nlm.nih.gov/SNP/. PCR reaction of each SNPs was performed in a total volume of 25 l using GoTaqMix® Green Master Mix (Promega, USA) which contained GoTaq® DNA polymerase in 1× Green GoTag® reaction buffer (pH 8.5), 200 M dNTPs, 2.5 mM MgCl2 (rs11146020) and 2 mM (rs1126442), and 10 pmol of each primer (rs11146020 forward: 5 -GTCCAGTTTCCAGGCTCTC3 , reverse: 5 -CTCCCCACAAGGTTCAGAAA-3 and rs1126442 forward: 5 -ACGGGCTCTGAGTCGCAT-3 , reverse: 5 GAAGTAACAGTGTCCAGAGGATG-3 ). The cycling conditions consisted of denaturation at 95 ◦ C for 1 min (rs11146020) and 94 ◦ C for 3 min (rs1126442), 35 cycles at 94–95 ◦ C for 30 s, 57 ◦ C (rs11146020) and 58 ◦ C (rs1126442) for 30 s, 72 ◦ C for 25 s and a final extension at 72 ◦ C for 5 min. The genotype of each SNP was then detected by Restriction Fragment Length Polymorphism (RFLP) analysis. 10–15 l of each amplified product was incubated with 0.5–1 U of specific restriction enzyme (BseRI for rs11146020 and BtgI for rs1126442). The amplicon of rs11146020 was digested into 96 bp and 55 bp fragments when the G allele was present, while the C allele presented as a 151 bp fragment. For rs1126442, the amplicon was cut in 352 bp, 86 bp and 62 bp fragments for G allele and 352 bp and 148 bp fragments for A allele. The DNA fragments were identified by 2.5% agarose gel electrophoresis and subsequently visualized with ethidium bromide staining. All genotyping was repeated on a separate occasion to confirm the result; any discrepancies were resolved after a further repetition. 2.3. Statistics Statistical differences in genotype and allele frequencies between patients and controls in both SNPs were evaluated using Fisher’s exact test in SPSS version 11.5 Software (Statistical Package for Social Science, SPSS, Inc., Chicago, IL) for single-SNP analysis. Analysis of the Hardy-Weinberg equilibrium (HWE) and, pair-wise linkage disequilibrium (LD) was carried out using SHEsis software (http://analysis2.bio-x.cn/myAnalysis.php). All statistical significances were considered at P-value <0.05. 3. Results Neither rs11146020 nor rs1126442 SNPs of GRIN1 significantly deviated from Hardy-Weinberg equilibrium in patient or control groups. Pair-wise linkage disequilibrium of rs11146020 and rs1126442 gave values of D = 0.078, r = −0.024 and global haplotype association P-value = 0.32, providing no evidence for linkage disequilibrium between the two SNPs. Fisher’s exact test showed that the genotype and allele frequencies between patients and controls were not statistically significant for either polymorphism (Table 1). When METH dependent patients were divided into those with and without psychosis, the genotype and allele frequencies of rs1126442, but not of rs11146020, showed strong and highly significant differences in distribution, in which the minor A allele was strongly associated with the absence of psychosis.
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R. Chanasong et al. / Neuroscience Letters 551 (2013) 58–61
Table 1 Genotype and allele frequencies of the two polymorphisms of GRIN1. Pa
SNP subjects
n
Genotype count (frequency)
rs11146020 (G1001C) Controls Patients With psychosis Without psychosis
103 100 53 47
G/G 65 (0.63) 56 (0.56) 32 (0.61) 24 (0.51)
G/C 33 (0.32) 35 (0.35) 16 (0.30) 19 (0.40)
C/C 5 (0.05) 9 (0.09) 5 (0.09) 4 (0.09)
rs1126442 (G2108A) Controls Patients With psychosis Without psychosis
103 100 53 47
G/G 54 (0.52) 62 (0.62) 50 (0.94) 12 (0.26)
G/A 46 (0.45) 36 (0.36) 2 (0.04) 34 (0.72)
A/A 3 (0.03) 2 (0.02) 1 (0.02) 1 (0.02)
Pb
Allele count (frequency)
Pa
0.401
0.303 0.348
C 43 (0.21) 53 (0.26) 26 (0.24) 27 (0.29)
0.182
0.571
G 163 (0.79) 147 (0.74) 80 (0.76) 67 (0.71) G 154 (0.75) 160 (0.80) 102 (0.96) 58 (0.62)
A 52 (0.25) 40 (0.20) 4 (0.04) 36 (0.38)
0.207
0.357
0.168
<0.0001
<0.0001
0.502
<0.0001
a
Patients vs. controls, or with psychosis vs. without psychosis. G/G homozygotes vs. minor allele carriers. Bold values are significant. b
4. Discussion Of the two hypotheses tested here, no support was found for an association of genetic variation in GRIN1 with METH dependence, but a very strong association of one GRIN1 SNP with presence of psychosis in METH-dependent subjects was identified. The present results provide further genetic evidence for involvement of the glutamatergic system in psychosis in patients with METH dependence. The rs1126442 SNP in GRIN1 is strongly associated with vulnerability to psychosis in these subjects, in which the presence of the A allele appears to have a protective effect on the emergence of psychosis in this Thai population. We did not observe a significant association of the rs11146020 SNP with METH dependence or with psychosis in METH dependence, in contrast to several previous reported associations with schizophrenia [3,6,7,25,28,41]. Some previous studies of schizophrenia have provided evidence that rs1126442 is not apparently associated with schizophrenia, including studies in Asian samples [25,29]. Additionally, no association was found in a Caucasian sample [23] although rs1126442 has been reported in association with substance abuse, albeit that of alcohol, in a Caucasian population [27,38]. In these studies, carriage of the A allele provides risk of alcohol abuse and some of its consequences, in contrast to our findings of a possible protective role of this allele against drug-induced psychosis. However, we should not attempt to draw conclusions from comparison between studies that differ both in ethnicity of the sample and in the substances of abuse, between which much of the underlying neurobiology inevitably differs. The rs11146020 (G1001C) SNP is located in the 5 UTR of GRIN1 gene, and its previously observed association with schizophrenia may relate to an effect on gene transcription or translation [41]. We hypothesized this SNP to contribute genetic risk to psychosis in METH dependence, which often exhibits schizophrenia-like symptoms. While the study was powered to identify a strong association with METH dependence, and had moderate power to detect a strong association with psychosis, the absence of a positive finding suggests that any effect of this gene on either METH dependence or METH-induced psychosis is likely to be weak in the Thai population. The current study is limited in several respects of which perhaps the most apparent is sample size, an inevitable consequence of collecting a well-characterised series of subjects with METH dependence and Thai ethnicity. Power analysis is difficult in the absence of prior equivalent investigations; sample size limited the power of our study to identify other than strong associations equivalent to or greater than the effects found in the largest association study of GRIN1 in schizophrenia in an Asian population [41]. Of the many SNPs within this gene, we restricted the study to two we considered the best candidates which had previously been associated with schizophrenia or addictive behaviour, thereby limiting
concerns over multiple testing. Applying a Bonferroni correction associated with two a priori hypotheses – association with METH dependence and association with psychosis within METH dependence – and two polymorphisms, both genotype and allele effects of rs1126442 on psychosis in METH dependence remain highly significant. We recognize that the two polymorphisms, chosen on the basis of previous studies, reflect only a small amount of the genetic variation in GRIN1; our preliminary finding with rs1126442 justifies the investigation of a more representative series of GRIN1 SNPs, and the eventually identification of the functional relationship between GRIN1 genotype and the phenotype of METH-dependent psychosis. We have studied a sample of males only; this reflects the fact that the great majority of METH abuse in Southeast Asia is by men. Clearly confirmation of these results with a larger sample within the Thai ethnic group would be valuable, and investigation in other ethnicities would also determine whether the findings have more general applicability. Nevertheless, if confirmed, these findings do indicate the possible role of the glutamatergic system, in particular NMDA receptor function, in METH-induced psychosis. Genes that are risk factors for schizophrenia; including G72 [14] and dysbindin [13] have been associated with METH psychosis, while neuregulin 1, another schizophrenia risk factor, is associated with METH dependence in a genome wide association study [34]. These findings do suggest a genetic commonality between schizophrenia and METH-dependent psychosis, and perhaps other psychotic disorders [13], involving genes affecting synaptic, particularly glutamatergic neurotransmission. It is notable that these previous studies on METH psychosis have not included a non-psychotic METH-dependent subgroup, as we have in this investigation, and thus those previous studies are not usually able to distinguish association with METH psychosis from association with METH dependence, which we clearly show to differ in our sample. A similarly powered study [4] investigating a population of Caucasian non-psychotic METH-dependent subjects, failed to find strong evidence replicating previously reported associations in Asians of six genes, none of which were directly related to glutamatergic neurotransmission. It is apparent that an understanding of the genetic factors that might underlie METH dependence remains elusive. However, the current association study between genetic variation of GRIN1 and METH dependence in a Thai population suggested that GRIN1 may play a role as a vulnerability gene for METH-dependent psychosis. Acknowledgements The research was supported by a grant from the Thailand Research Fund (TRF) and Commission of Higher Education (CHE)
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to SNT and ST, with additional support from a British Council PMI2 collaborative grant to GPR and SNT. RC was supported by a Ph.D. studentship under the staff development project of Naresuan University. The authors also gratefully acknowledge all patients and volunteers participated in this study as well as the Central Correctional Institution for Drug Addicts, Bangkok, Thailand. We thank the Faculty of Medical Science, Naresuan University, Thailand for facility support. Special thanks to Ms. Sukanya Horpaopan and Ms. Siriluk Weerasakul for their technical supports. References [1] American Psychiatric Association, Diagnosis and Statistical Manual of Mental Disorders, 4th ed., American Psychiatric Association, Washington, DC, 1994. [2] K. Akiyama, A. Kanzaki, K. Tsuchida, H. Ujike, Methamphetamine-induced behavioral sensitization and its implications for relapse of schizophrenia, Schizophrenia Research 12 (3) (1994) 251–257. [3] S. Begni, S. Moraschi, S. Bignotti, F. Fumagalli, L. 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Genetic variation of GRIN1 confers vulnerability to methamphetamine-dependent psychosis in a Thai population Rachanee Chanasong a , Samur Thanoi a,b , Paritat Watiktinkorn c , Gavin P. Reynolds d , Sutisa Nudmamud-Thanoi a,b,∗ a
Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand Centre of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand c Synphaet Hospital, Bangkok, Thailand d Biomedical Research Centre, Sheffield Hallam University, Sheffield, UK b
h i g h l i g h t s • • • •
A cohort of male METH dependence with psychosis was genotyped for two SNPs in GRIN1. G2108A SNP showed a very strong association with METH-induced psychosis. These results identify a potential risk factor for drug-induced psychosis. Genetic variation in glutamate system plays a role in the emergence of psychosis.
a r t i c l e
i n f o
Article history: Received 28 May 2013 Received in revised form 5 July 2013 Accepted 9 July 2013 Keywords: Pharmacogenetics GRIN1 Methamphetamine Psychosis Substance misuse
a b s t r a c t GRIN1 is a gene that encodes the N-methyl-d aspartate (NMDA) receptor subunit1 (NR1). Variations of GRIN1 have been identified as a risk factor for schizophrenia and drug dependence, supporting hypotheses of glutamatergic dysfunction in these disorders. Methamphetamine (METH) is a psychostimulant drug which can induce psychotic symptoms reminiscent of those found in schizophrenia; thus GRIN1 is a candidate gene for vulnerability to METH dependence or METH-dependent psychosis. The present study examined two polymorphisms of GRIN1, rs11146020 (G1001C) and rs1126442 (G2108A), in 100 male Thai METH-dependent patients and 103 healthy controls using PCR-RFLP techniques. Neither polymorphism was significantly associated with METH dependence, although rs1126442 was highly significantly associated with METH-dependent psychosis, in which the A allele showed reduced frequency (P < 0.00001). The present findings indicate that the rs1126442 of GRIN1 contributes to the genetic vulnerability to psychosis in METH-dependent subjects in the Thai population. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The fundamental pathophysiology of drug dependence is thought to involve dysfunction of the mesolimbic dopamine system underlying reward mechanisms [19,20,37,39]. However, increasing evidence indicates a role for the glutamatergic system, and particularly the NMDA receptor, in drug addiction [10,11,33,36]. Methamphetamine (METH) is a derivative of amphetamine which is classified as one of the psychostimulant group of addictive drugs. METH can induce psychotic symptoms which closely resemble schizophrenia [2,35]. In addition, METH administration
∗ Corresponding author at: Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand. Tel.: +66 55 964 672; fax: +66 55 964 770. E-mail address: [email protected] (S. Nudmamud-Thanoi). 0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.07.017
can induce behavioural sensitization which has been useful as an animal model of schizophrenia [5,17]. Certainly, there is substantial evidence implicating a dysfunction of glutamatergic neurotransmission in schizophrenia [21,22,24,32]. Therefore, METH dependence, or particularly the psychosis associated with METH dependence, may share some common underlying glutamatergic neuropathology with schizophrenia. N-methyl-d aspartate (NMDA) receptors are ionotropic glutamate receptors that play important roles in neurodevelopment and learning and memory [9,26]. In humans, the NR1 receptor subunit is translated from the GRIN1 gene which is located on chromosome 9q34.3 and is composed of 21 exons. It is required as a key receptor subunit for physiological function combined with one or more of the four NR2 subunits NMDAR2A–D to make the heterodimeric receptor complex [8,15,18,30]. Numerous studies have indicated a dysfunction of NR1 in both schizophrenia and drug
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abuse, particularly METH dependence. In METH-sensitized rats, it was found that NR1, NR2A, and NR2B proteins in the striatum were decreased [40]. Similarly, amphetamine exposure for 5 days and after 14 days of withdrawal exhibited decreased NR1 mRNA and protein in the nucleus accumbens but with increases in prefrontal cortex [16]. Following acute METH treatment, decreased expression of NR1 was found in the frontal cortex while NR2A was increased [31]. Additionally, in other studies where METH was given as either acute or subacute administration, an elevation of NR1 immunoreactivity (IR) was found in the striatum, whereas increased NR1-IR in the frontal cortex was only found in the subacute group [11]. A further approach to understanding how glutamate mechanisms contribute to drug dependence is its association with genetic variation; i.e. how single nucleotide polymorphisms (SNPs) in genes involved in glutamatergic function may contribute to individual differences in vulnerability to drug dependence. In alcohol studies, alcohol-associated anxiolysis and motor impairment were reduced in NR1 mutant mice by a reduction of glycine binding sites [12]. Interestingly, association studies in German alcoholics found the A allele of the G2108A SNP (rs1126442) in exon 7 of the NR1 gene (GRIN1) was more common in patients than in controls [27,38]. Furthermore, there are several studies in which SNPs of NMDA receptor genes were reported to be associated with elevated risk in schizophrenia. An increased frequency of the C allele of rs11146020 is reported in schizophrenia in various ethnicities [3,6,41]. This observation was found to be particularly in a subgroup with a lifetime history of depressive symptoms [7]. Additionally, this SNP has revealed an interaction with SNPs in the NR2B gene (GRIN2B), T4197C and T5988C, to confer vulnerability to the disease [25], and a meta-analysis also concluded that the C allele of rs11146020 may be a marker for a high risk for developing schizophrenia [28]. Taken together, this evidence suggests that genetic variation of GRIN1 provides a good candidate for association with METH dependence and its resultant psychosis. We have chosen to test these hypotheses in a Thai population in which METH abuse and dependence is a major social and medical concern. The present study therefore hypothesized that the genetic variation in two SNPs of GRIN1, rs11146020 (G1001C) and rs1126442 (G2108A), may confer susceptibility to METH dependence and METH psychosis in the Thai population.
2. Materials and methods 2.1. Subjects Subjects comprised 100 Thai METH dependent patients recruited from the Central Correctional Institution for Drug Addicts, Bangkok, Thailand, meeting criteria for METH dependence according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria [1]. Subjects were divided into those with or without a history of psychotic symptoms considered to be due to METH use. Psychiatric symptoms were treated according to local practice with antipsychotic, antidepressant or anxiolytic drugs as appropriate. 103 Thai control subjects were recruited, excluding those with a history of drug misuse or psychiatric disorder. Subjects were all male and age-matched (mean age ± SD 29.45 ± 4.55, range 21–45 years in patients, and 28.75 ± 6.39, range 20–46 years in controls). The average age of onset of METH use in patients was 19.52 ± 6.53, range 12–41 years, and the duration of METH use was 9.35 ± 5.26, range 1–23 years. All participants were informed with a complete and extensive explanation of the study, and signed consent forms approved by the Ethical Committees of Naresuan University, Thailand.
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2.2. SNP genotyping Blood samples from both patients and controls were obtained by fingertip venipuncture and were collected on FTA® cards (Whatman, WB120305, USA). The cards were washed with FTA purification reagent (Whatman, WB1202045, USA) until clear to obtain genomic DNA. PCR primers specific to rs11146020 (G1001C) in the 5 UTR region and rs1126442 (G2108A) in exon 7 of GRIN1 were designed based on the sequence and information from dbSNP database http://www.ncbi.nlm.nih.gov/SNP/. PCR reaction of each SNPs was performed in a total volume of 25 l using GoTaqMix® Green Master Mix (Promega, USA) which contained GoTaq® DNA polymerase in 1× Green GoTag® reaction buffer (pH 8.5), 200 M dNTPs, 2.5 mM MgCl2 (rs11146020) and 2 mM (rs1126442), and 10 pmol of each primer (rs11146020 forward: 5 -GTCCAGTTTCCAGGCTCTC3 , reverse: 5 -CTCCCCACAAGGTTCAGAAA-3 and rs1126442 forward: 5 -ACGGGCTCTGAGTCGCAT-3 , reverse: 5 GAAGTAACAGTGTCCAGAGGATG-3 ). The cycling conditions consisted of denaturation at 95 ◦ C for 1 min (rs11146020) and 94 ◦ C for 3 min (rs1126442), 35 cycles at 94–95 ◦ C for 30 s, 57 ◦ C (rs11146020) and 58 ◦ C (rs1126442) for 30 s, 72 ◦ C for 25 s and a final extension at 72 ◦ C for 5 min. The genotype of each SNP was then detected by Restriction Fragment Length Polymorphism (RFLP) analysis. 10–15 l of each amplified product was incubated with 0.5–1 U of specific restriction enzyme (BseRI for rs11146020 and BtgI for rs1126442). The amplicon of rs11146020 was digested into 96 bp and 55 bp fragments when the G allele was present, while the C allele presented as a 151 bp fragment. For rs1126442, the amplicon was cut in 352 bp, 86 bp and 62 bp fragments for G allele and 352 bp and 148 bp fragments for A allele. The DNA fragments were identified by 2.5% agarose gel electrophoresis and subsequently visualized with ethidium bromide staining. All genotyping was repeated on a separate occasion to confirm the result; any discrepancies were resolved after a further repetition. 2.3. Statistics Statistical differences in genotype and allele frequencies between patients and controls in both SNPs were evaluated using Fisher’s exact test in SPSS version 11.5 Software (Statistical Package for Social Science, SPSS, Inc., Chicago, IL) for single-SNP analysis. Analysis of the Hardy-Weinberg equilibrium (HWE) and, pair-wise linkage disequilibrium (LD) was carried out using SHEsis software (http://analysis2.bio-x.cn/myAnalysis.php). All statistical significances were considered at P-value <0.05. 3. Results Neither rs11146020 nor rs1126442 SNPs of GRIN1 significantly deviated from Hardy-Weinberg equilibrium in patient or control groups. Pair-wise linkage disequilibrium of rs11146020 and rs1126442 gave values of D = 0.078, r = −0.024 and global haplotype association P-value = 0.32, providing no evidence for linkage disequilibrium between the two SNPs. Fisher’s exact test showed that the genotype and allele frequencies between patients and controls were not statistically significant for either polymorphism (Table 1). When METH dependent patients were divided into those with and without psychosis, the genotype and allele frequencies of rs1126442, but not of rs11146020, showed strong and highly significant differences in distribution, in which the minor A allele was strongly associated with the absence of psychosis.
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Table 1 Genotype and allele frequencies of the two polymorphisms of GRIN1. Pa
SNP subjects
n
Genotype count (frequency)
rs11146020 (G1001C) Controls Patients With psychosis Without psychosis
103 100 53 47
G/G 65 (0.63) 56 (0.56) 32 (0.61) 24 (0.51)
G/C 33 (0.32) 35 (0.35) 16 (0.30) 19 (0.40)
C/C 5 (0.05) 9 (0.09) 5 (0.09) 4 (0.09)
rs1126442 (G2108A) Controls Patients With psychosis Without psychosis
103 100 53 47
G/G 54 (0.52) 62 (0.62) 50 (0.94) 12 (0.26)
G/A 46 (0.45) 36 (0.36) 2 (0.04) 34 (0.72)
A/A 3 (0.03) 2 (0.02) 1 (0.02) 1 (0.02)
Pb
Allele count (frequency)
Pa
0.401
0.303 0.348
C 43 (0.21) 53 (0.26) 26 (0.24) 27 (0.29)
0.182
0.571
G 163 (0.79) 147 (0.74) 80 (0.76) 67 (0.71) G 154 (0.75) 160 (0.80) 102 (0.96) 58 (0.62)
A 52 (0.25) 40 (0.20) 4 (0.04) 36 (0.38)
0.207
0.357
0.168
<0.0001
<0.0001
0.502
<0.0001
a
Patients vs. controls, or with psychosis vs. without psychosis. G/G homozygotes vs. minor allele carriers. Bold values are significant. b
4. Discussion Of the two hypotheses tested here, no support was found for an association of genetic variation in GRIN1 with METH dependence, but a very strong association of one GRIN1 SNP with presence of psychosis in METH-dependent subjects was identified. The present results provide further genetic evidence for involvement of the glutamatergic system in psychosis in patients with METH dependence. The rs1126442 SNP in GRIN1 is strongly associated with vulnerability to psychosis in these subjects, in which the presence of the A allele appears to have a protective effect on the emergence of psychosis in this Thai population. We did not observe a significant association of the rs11146020 SNP with METH dependence or with psychosis in METH dependence, in contrast to several previous reported associations with schizophrenia [3,6,7,25,28,41]. Some previous studies of schizophrenia have provided evidence that rs1126442 is not apparently associated with schizophrenia, including studies in Asian samples [25,29]. Additionally, no association was found in a Caucasian sample [23] although rs1126442 has been reported in association with substance abuse, albeit that of alcohol, in a Caucasian population [27,38]. In these studies, carriage of the A allele provides risk of alcohol abuse and some of its consequences, in contrast to our findings of a possible protective role of this allele against drug-induced psychosis. However, we should not attempt to draw conclusions from comparison between studies that differ both in ethnicity of the sample and in the substances of abuse, between which much of the underlying neurobiology inevitably differs. The rs11146020 (G1001C) SNP is located in the 5 UTR of GRIN1 gene, and its previously observed association with schizophrenia may relate to an effect on gene transcription or translation [41]. We hypothesized this SNP to contribute genetic risk to psychosis in METH dependence, which often exhibits schizophrenia-like symptoms. While the study was powered to identify a strong association with METH dependence, and had moderate power to detect a strong association with psychosis, the absence of a positive finding suggests that any effect of this gene on either METH dependence or METH-induced psychosis is likely to be weak in the Thai population. The current study is limited in several respects of which perhaps the most apparent is sample size, an inevitable consequence of collecting a well-characterised series of subjects with METH dependence and Thai ethnicity. Power analysis is difficult in the absence of prior equivalent investigations; sample size limited the power of our study to identify other than strong associations equivalent to or greater than the effects found in the largest association study of GRIN1 in schizophrenia in an Asian population [41]. Of the many SNPs within this gene, we restricted the study to two we considered the best candidates which had previously been associated with schizophrenia or addictive behaviour, thereby limiting
concerns over multiple testing. Applying a Bonferroni correction associated with two a priori hypotheses – association with METH dependence and association with psychosis within METH dependence – and two polymorphisms, both genotype and allele effects of rs1126442 on psychosis in METH dependence remain highly significant. We recognize that the two polymorphisms, chosen on the basis of previous studies, reflect only a small amount of the genetic variation in GRIN1; our preliminary finding with rs1126442 justifies the investigation of a more representative series of GRIN1 SNPs, and the eventually identification of the functional relationship between GRIN1 genotype and the phenotype of METH-dependent psychosis. We have studied a sample of males only; this reflects the fact that the great majority of METH abuse in Southeast Asia is by men. Clearly confirmation of these results with a larger sample within the Thai ethnic group would be valuable, and investigation in other ethnicities would also determine whether the findings have more general applicability. Nevertheless, if confirmed, these findings do indicate the possible role of the glutamatergic system, in particular NMDA receptor function, in METH-induced psychosis. Genes that are risk factors for schizophrenia; including G72 [14] and dysbindin [13] have been associated with METH psychosis, while neuregulin 1, another schizophrenia risk factor, is associated with METH dependence in a genome wide association study [34]. These findings do suggest a genetic commonality between schizophrenia and METH-dependent psychosis, and perhaps other psychotic disorders [13], involving genes affecting synaptic, particularly glutamatergic neurotransmission. It is notable that these previous studies on METH psychosis have not included a non-psychotic METH-dependent subgroup, as we have in this investigation, and thus those previous studies are not usually able to distinguish association with METH psychosis from association with METH dependence, which we clearly show to differ in our sample. A similarly powered study [4] investigating a population of Caucasian non-psychotic METH-dependent subjects, failed to find strong evidence replicating previously reported associations in Asians of six genes, none of which were directly related to glutamatergic neurotransmission. It is apparent that an understanding of the genetic factors that might underlie METH dependence remains elusive. However, the current association study between genetic variation of GRIN1 and METH dependence in a Thai population suggested that GRIN1 may play a role as a vulnerability gene for METH-dependent psychosis. Acknowledgements The research was supported by a grant from the Thailand Research Fund (TRF) and Commission of Higher Education (CHE)
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to SNT and ST, with additional support from a British Council PMI2 collaborative grant to GPR and SNT. RC was supported by a Ph.D. studentship under the staff development project of Naresuan University. The authors also gratefully acknowledge all patients and volunteers participated in this study as well as the Central Correctional Institution for Drug Addicts, Bangkok, Thailand. We thank the Faculty of Medical Science, Naresuan University, Thailand for facility support. Special thanks to Ms. Sukanya Horpaopan and Ms. Siriluk Weerasakul for their technical supports. References [1] American Psychiatric Association, Diagnosis and Statistical Manual of Mental Disorders, 4th ed., American Psychiatric Association, Washington, DC, 1994. [2] K. Akiyama, A. Kanzaki, K. Tsuchida, H. Ujike, Methamphetamine-induced behavioral sensitization and its implications for relapse of schizophrenia, Schizophrenia Research 12 (3) (1994) 251–257. [3] S. Begni, S. Moraschi, S. Bignotti, F. Fumagalli, L. 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