Brief association letter 135
Association of GRIN1, ABCB1, and DRD4 genes and response to antipsychotic drug treatment in schizophrenia Pranita Paia, Praveen Arathilb, Ananthapadmanabha Kotambaila, Rajesh Nairb, Meenal Guptad, Nagaraj S. Moilyc, Ritushree Kukretid, Sanjeev Jainc, Padmalatha S. Raia, Puthiya M. Gopinatha, Podila S. Sharmab and Kapaettu Satyamoorthya Psychiatric Genetics 2015, 25:135–136 a
b
Department of Biotechnology, School of Life Sciences, Department of Psychiatry, Kasturba Medical College, Manipal University, Manipal, cNational Institute of Mental Health and Neurosciences, Bangalore, Karnataka and dCSIRInstitute of Genomics and Integrative Biology, New Delhi, India
Correspondence to Kapaettu Satyamoorthy, PhD, Department of Biotechnology, School of Life Sciences, Manipal University, Planetarium Complex, Manipal 576104, Karnataka, India Tel: + 91 820 2922058/ + 91 820 2571925; fax: + 91 820 2571919; e-mail: [email protected] Received 21 May 2014 Revised 24 November 2014 Accepted 20 January 2015
Genetic polymorphisms in dopamine receptors as well as the multidrug resistance genes have been implicated reiteratively as candidate genes for predisposition and for treatment response in schizophrenia (Arranz et al., 2011; Brandl et al., 2014). Glutamate receptor ionotropic N-methyl D-aspartate 1 (GRIN1) genetic variants are considered as a strong candidate for the etiology of schizophrenia, but its relationship with drug response has not yet been investigated (Zhao et al., 2006; Galehdari et al., 2009). The ambiguous genetic findings reported in different studies make it necessary to investigate the role of these genes in multiple populations.
response, 75 fulfilled the criteria of poor responders. We have also included 136 healthy controls in the study.
The aim of the present study was to examine the association of important single nucleotide polymorphisms (SNPs) of three genes namely dopamine receptor D4 (DRD4), ATP-binding cassette, sub-family B member 1 (ABCB1), and GRIN1, in an Indian cohort of schizophrenic patients characterized for antipsychotic drug response.
The distribution of genotypes on the basis of the severity of illness scores (CGI-S) for risperidone-treated patients showed significant differences among the genotypes of rs1045642 (CC vs. CT, P = 0.0004; CC vs. TT, P = 0.006; n = 43 in group 1 and n = 92 in group 2), rs1128503 (CC vs. CT, P = 0.03; n = 42 in group 1 and n = 92 in group 2), and rs4646984 (120 bp/120 bp vs. 120 bp/240 bp, P = 0.04; n = 43 in group 1 and n = 88 in group 2) (refer figure 1A–F in the Supplemental digital content 1, http://links.lww.com/ PG/A128). No significant differences were observed in the genotype, allele, or haplotype distributions of any polymorphism with antipsychotic drug response groups.
Clinical patients were diagnosed using the criteria described in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR). The most frequently administered antipsychotic drugs were risperidone and olanzapine. Treatment response was measured using the Clinical Global Impressions Severity scores (CGI-S) (Guy, 1976). Adequate control of symptoms was defined as a CGI-S score of 2 or less (borderline mentally ill). If the symptoms continued (CGI-S ≥ 3), treatment was modified in accordance with guidelines and they were evaluated again after 12 weeks. A decrease in CGI-S scores by 2 points was qualified as an appropriate response. Those who continued to have scores of 3 or above were classified as poor responders to antipsychotic treatment. Among 195 patients evaluated for drug Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.psychgenetics.com). 0955-8829 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Genotyping of rs1045642 and rs2032582 (ABCB1), rs1800955 and rs4646984 (DRD4), and rs11146020 (GRIN1) were carried out using standard PCR and restriction fragment length polymorphism, followed by confirmatory DNA sequencing methods (see table 1 in the Supplemental digital content 1, http://links.lww.com/PG/A128). Analysis of allele genotype and haplotype frequencies between the participant groups was carried out using Fisher’s exact test. Risk association was calculated by odds ratio (ORs) with 95% confidence intervals (CIs).
Comparative analysis of polymorphisms between cases and healthy controls showed no significant risk for schizophrenia at the GRIN1 rs11146020 ‘C’ allele [OR = 0.68 (95% CI 0.49–0.95), P = 0.02, n = 195 cases and 130 controls] and the DRD4 rs1800955 ‘C’ allele [OR = 0.7 (95% CI 0.51–0.97) P = 0.04, n = 181 cases and 132 controls] (see table 4 in the Supplemental digital content 1, http:// links.lww.com/PG/A128). Haplotype analysis of DRD4 polymorphisms rs1800955 ‘T’ allele and the rs4646984 120 bp allele showed a significant risk for schizophrenia [OR = 1.56 (95% CI 1.02–2.39), P = 0.04, n = 177 cases and 114 controls] (refer table 5 in the Supplemental digital content 1, http://links.lww.com/PG/A128). DOI: 10.1097/YPG.0000000000000079
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
136 Psychiatric Genetics 2015, Vol 25 No 3
Our study explains the possible influence of DRD4 and GRIN1 SNPs on schizophrenia susceptibility and ABCB1 SNPs on disease severity. However, there was no significant evidence of an association for any of the SNPs examined with antipsychotic drug response in our population.
Acknowledgements The authors thank the financial and infrastructural support by the Department of Biotechnology (DBT), and TIFAC-CORE in Pharmacogenomics, Government of India. They also thank the Indian Council of Medical Research, Government of India, for their financial support.
Conflicts of interest
There are no conflicts of interest.
References Arranz MJ, Rivera M, Munro JC (2011). Pharmacogenetics of response to antipsychotics in patients with schizophrenia. CNS Drugs 25:933–969. Brandl EJ, Kennedy JL, Muller DJ (2014). Pharmacogenetics of antipsychotics. Can J Psychiatry 59:76–88. Galehdari H, Pooryasin A, Foroughmand A, Daneshmand S, Saadat M (2009). Association between the G1001C polymorphism in the GRIN1 gene promoter and schizophrenia in the Iranian population. J Mol Neurosci 38:178–181. Guy W (1976). ECDEU assessment manual for psychopharmacology: US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, Rockville, MD: National Institute of Mental Health. Zhao X, Li H, Shi Y, Tang R, Chen W, Liu J, et al. (2006). Significant association between the genetic variations in the 5′ end of the N-methyl-D-aspartate receptor subunit gene GRIN1 and schizophrenia. Biol Psychiatry 59: 747–753.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Association of GRIN1, ABCB1, and DRD4 genes and response to antipsychotic drug treatment in schizophrenia Pranita Paia, Praveen Arathilb, Ananthapadmanabha Kotambaila, Rajesh Nairb, Meenal Guptad, Nagaraj S. Moilyc, Ritushree Kukretid, Sanjeev Jainc, Padmalatha S. Raia, Puthiya M. Gopinatha, Podila S. Sharmab and Kapaettu Satyamoorthya Psychiatric Genetics 2015, 25:135–136 a
b
Department of Biotechnology, School of Life Sciences, Department of Psychiatry, Kasturba Medical College, Manipal University, Manipal, cNational Institute of Mental Health and Neurosciences, Bangalore, Karnataka and dCSIRInstitute of Genomics and Integrative Biology, New Delhi, India
Correspondence to Kapaettu Satyamoorthy, PhD, Department of Biotechnology, School of Life Sciences, Manipal University, Planetarium Complex, Manipal 576104, Karnataka, India Tel: + 91 820 2922058/ + 91 820 2571925; fax: + 91 820 2571919; e-mail: [email protected] Received 21 May 2014 Revised 24 November 2014 Accepted 20 January 2015
Genetic polymorphisms in dopamine receptors as well as the multidrug resistance genes have been implicated reiteratively as candidate genes for predisposition and for treatment response in schizophrenia (Arranz et al., 2011; Brandl et al., 2014). Glutamate receptor ionotropic N-methyl D-aspartate 1 (GRIN1) genetic variants are considered as a strong candidate for the etiology of schizophrenia, but its relationship with drug response has not yet been investigated (Zhao et al., 2006; Galehdari et al., 2009). The ambiguous genetic findings reported in different studies make it necessary to investigate the role of these genes in multiple populations.
response, 75 fulfilled the criteria of poor responders. We have also included 136 healthy controls in the study.
The aim of the present study was to examine the association of important single nucleotide polymorphisms (SNPs) of three genes namely dopamine receptor D4 (DRD4), ATP-binding cassette, sub-family B member 1 (ABCB1), and GRIN1, in an Indian cohort of schizophrenic patients characterized for antipsychotic drug response.
The distribution of genotypes on the basis of the severity of illness scores (CGI-S) for risperidone-treated patients showed significant differences among the genotypes of rs1045642 (CC vs. CT, P = 0.0004; CC vs. TT, P = 0.006; n = 43 in group 1 and n = 92 in group 2), rs1128503 (CC vs. CT, P = 0.03; n = 42 in group 1 and n = 92 in group 2), and rs4646984 (120 bp/120 bp vs. 120 bp/240 bp, P = 0.04; n = 43 in group 1 and n = 88 in group 2) (refer figure 1A–F in the Supplemental digital content 1, http://links.lww.com/ PG/A128). No significant differences were observed in the genotype, allele, or haplotype distributions of any polymorphism with antipsychotic drug response groups.
Clinical patients were diagnosed using the criteria described in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR). The most frequently administered antipsychotic drugs were risperidone and olanzapine. Treatment response was measured using the Clinical Global Impressions Severity scores (CGI-S) (Guy, 1976). Adequate control of symptoms was defined as a CGI-S score of 2 or less (borderline mentally ill). If the symptoms continued (CGI-S ≥ 3), treatment was modified in accordance with guidelines and they were evaluated again after 12 weeks. A decrease in CGI-S scores by 2 points was qualified as an appropriate response. Those who continued to have scores of 3 or above were classified as poor responders to antipsychotic treatment. Among 195 patients evaluated for drug Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.psychgenetics.com). 0955-8829 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Genotyping of rs1045642 and rs2032582 (ABCB1), rs1800955 and rs4646984 (DRD4), and rs11146020 (GRIN1) were carried out using standard PCR and restriction fragment length polymorphism, followed by confirmatory DNA sequencing methods (see table 1 in the Supplemental digital content 1, http://links.lww.com/PG/A128). Analysis of allele genotype and haplotype frequencies between the participant groups was carried out using Fisher’s exact test. Risk association was calculated by odds ratio (ORs) with 95% confidence intervals (CIs).
Comparative analysis of polymorphisms between cases and healthy controls showed no significant risk for schizophrenia at the GRIN1 rs11146020 ‘C’ allele [OR = 0.68 (95% CI 0.49–0.95), P = 0.02, n = 195 cases and 130 controls] and the DRD4 rs1800955 ‘C’ allele [OR = 0.7 (95% CI 0.51–0.97) P = 0.04, n = 181 cases and 132 controls] (see table 4 in the Supplemental digital content 1, http:// links.lww.com/PG/A128). Haplotype analysis of DRD4 polymorphisms rs1800955 ‘T’ allele and the rs4646984 120 bp allele showed a significant risk for schizophrenia [OR = 1.56 (95% CI 1.02–2.39), P = 0.04, n = 177 cases and 114 controls] (refer table 5 in the Supplemental digital content 1, http://links.lww.com/PG/A128). DOI: 10.1097/YPG.0000000000000079
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
136 Psychiatric Genetics 2015, Vol 25 No 3
Our study explains the possible influence of DRD4 and GRIN1 SNPs on schizophrenia susceptibility and ABCB1 SNPs on disease severity. However, there was no significant evidence of an association for any of the SNPs examined with antipsychotic drug response in our population.
Acknowledgements The authors thank the financial and infrastructural support by the Department of Biotechnology (DBT), and TIFAC-CORE in Pharmacogenomics, Government of India. They also thank the Indian Council of Medical Research, Government of India, for their financial support.
Conflicts of interest
There are no conflicts of interest.
References Arranz MJ, Rivera M, Munro JC (2011). Pharmacogenetics of response to antipsychotics in patients with schizophrenia. CNS Drugs 25:933–969. Brandl EJ, Kennedy JL, Muller DJ (2014). Pharmacogenetics of antipsychotics. Can J Psychiatry 59:76–88. Galehdari H, Pooryasin A, Foroughmand A, Daneshmand S, Saadat M (2009). Association between the G1001C polymorphism in the GRIN1 gene promoter and schizophrenia in the Iranian population. J Mol Neurosci 38:178–181. Guy W (1976). ECDEU assessment manual for psychopharmacology: US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, Rockville, MD: National Institute of Mental Health. Zhao X, Li H, Shi Y, Tang R, Chen W, Liu J, et al. (2006). Significant association between the genetic variations in the 5′ end of the N-methyl-D-aspartate receptor subunit gene GRIN1 and schizophrenia. Biol Psychiatry 59: 747–753.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
