Functional Genomics Unit, Institute of Genomics and Integrative Biology (Council of Scientific and Industrial Research), Mall Road, Delhi 110 007, India.

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Email the corresponding author at ritus@igib.res.in

Published Online:16 Mar 2009https://doi.org/10.2217/14622416.10.3.385

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Abstract

Aim: We investigated the catechol-O-methyltrasferase (COMT) gene, which is a strong functional and positional candidate gene for schizophrenia and therapeutic response to antipsychotic medication. Materials & methods: Single-locus as well as detailed haplotype-based association analysis of the COMT gene with schizophrenia and antipsychotic treatment response was carried out using seven COMT polymorphisms in 398 schizophrenia patients and 241 healthy individuals from a homogeneous south Indian population. Further responsiveness to risperidone treatment was assessed in 117 schizophrenia patients using Clinical Global Impressions (CGI). A total of 69 patients with a CGI score of 2 or less met the criteria of good responders and 48 were patients who continued to have a score of 3 and above and were classified as poor responders to risperidone treatment. Results: The association of SNP rs4680 with schizophrenia did not remain significant after adjusting for multiple testing. Haplotype analysis showed highly significant association of seven COMT marker haplotypes with schizophrenia (CLUMP T4 p-value = 0.0001). Our results also demonstrated initial significant allelic associations of two SNPs with drug response (rs4633: χ² = 4.36, p-value = 0.036, OR: 1.80, 95% CI: 1.03–3.15; and rs4680: χ² = 4.02, p-value = 0.044, OR: 1.76, 95% CI: 1.01–3.06) before multiple correction. We employed two-marker sliding window analysis for haplotype association and observed a significant association of markers located between intron 1 and intron 2 (rs737865, rs6269: CLUMP T4 p-value = 0.021); and in exon 4 (rs4818, rs4680: CLUMP T4 p-value = 0.028) with drug response. Conclusion: The present study thus indicates that the interacting effects within the COMT gene polymorphisms may influence the disease status and response to risperidone in schizophrenia patients. However, the study needs to be replicated in a larger sample set for confirmation, followed by functional studies.

Keywords:

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

Bibliography

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Medline CASGoogle Scholar
2 Shprintzen RJ, Goldberg R, Golding-Kushner KJ, Marion RW: Late-onset psychosis in the velo-cardio-facial syndrome. Am. J. Med. Genet.42,141–142 (1992).
Medline CASGoogle Scholar
3 Gothelf D, Schaer M, Eliez S: Genes, brain development and psychiatric phenotypes in velo-cardio-facial syndrome. Dev. Disabil. Res. Rev.14,59–68 (2008).
MedlineGoogle Scholar
4 Lotta T, Vidgren J, Tilgmann C et al.: Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry34,4202–4210 (1995).
Medline CASGoogle Scholar
5 Chen J, Lipska BK, Halim N et al.: Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am. J. Hum. Genet.75,807–821 (2004).
Medline CASGoogle Scholar
6 Palmatier MA, Kang AM, Kidd KK: Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol. Psychiatry46,557–567 (1999).▪ First global survey of frequency of COMT polymorphism (rs4680) undertaken in 30 diverse populations.
Medline CASGoogle Scholar
7 Chen X, Wang X, O’Neill AF, Walsh D, Kendler KS: Variants in the catechol-O-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families. Mol Psychiatry9,962–967 (2004).
Medline CASGoogle Scholar
8 Goghari VM, Sponheim SR: Differential association of the COMT Val158Met polymorphism with clinical phenotypes in schizophrenia and bipolar disorder. Schizophr. Res.103,186–191 (2008).
MedlineGoogle Scholar
9 Egan MF, Goldberg TE, Kolachana BS et al.: Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc. Natl Acad. Sci. USA98,6917–6922 (2001).
Medline CASGoogle Scholar
10 Woodward ND, Jayathilake K, Meltzer HY: COMT Val108/158Met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia. Schizophr. Res.90,86–96 (2007).
MedlineGoogle Scholar
11 Bilder RM, Volavka J, Lachman HM, Grace AA: The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology29,1943–1961 (2004).
Medline CASGoogle Scholar
12 Meyer-Lindenberg A, Kohn PD, Kolachana B et al.: Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat. Neurosci.8,594–596 (2005).
Medline CASGoogle Scholar
13 Tunbridge EM, Harrison PJ, Weinberger DR: Catechol-O-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol. Psychiatry60,141–151 (2006).
Medline CASGoogle Scholar
14 Semwal P, Prasad S, Varma PG, Bhagwat AM, Deshpande SN, Thelma BK: Candidate gene polymorphisms among North Indians and their association with schizophrenia in a case–control study. J. Genet.81,65–71 (2002).
Medline CASGoogle Scholar
15 Nunokawa A, Watanabe Y, Muratake T, Kaneko N, Koizumi M, Someya T: No associations exist between five functional polymorphisms in the catechol-O-methyltransferase gene and schizophrenia in a Japanese population. Neurosci. Res.58,291–296 (2007).
Medline CASGoogle Scholar
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Medline CASGoogle Scholar
17 Munafo MR, Bowes L, Clark TG, Flint J: Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies. Mol. Psychiatry10,765–770 (2005).
Medline CASGoogle Scholar
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Medline CASGoogle Scholar
19 Illi A, Kampman O, Hänninen K et al.: Catechol-O-methyltransferase Val108/158Met genotype and response to antipsychotic medication in schizophrenia. Hum. Psychopharmacol.22,211–215 (2007).
Medline CASGoogle Scholar
20 Molero P, Ortuno F, Zalacain M, Patino-Garcia A: Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment. Pharmacogenomics J.7,418–426 (2007).
Medline CASGoogle Scholar
21 Yamanouchi Y, Iwata N, Suzuki T, Kitajima T, Ikeda M, Ozaki N: Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone. Pharmacogenomics J.3,356–361 (2003).
Medline CASGoogle Scholar
22 Nolan KA, Czobor P, Citrome LL et al.: Catechol-O-methyltransferase and monoamine oxidase-A polymorphisms and treatment response to typical and atypical neuroleptics. J. Clin. psychopharmacol.26,338–340 (2006).
MedlineGoogle Scholar
23 Chen ML, Chen CH: Chronic antipsychotics treatment regulates MAOA, MAOB and COMT gene expression in rat frontal cortex. J. Psychiatr. Res.41,57–62 (2007).▪ Study demonstrated that different antipsychotic drugs may differentially regulate the gene expression of COMT, which may partly account for the molecular mechanism of their different clinical efficacy.
MedlineGoogle Scholar
24 Shifman S, Bronstein M, Sternfeld M et al.: A highly significant association between a COMT haplotype and schizophrenia. Am. J. Hum. Genet.71,1296–1302 (2002).▪ Highly significant association of a COMT haplotype was reported in a large population.
Medline CASGoogle Scholar
25 Handoko HY, Nyholt DR, Hayward NK et al.: Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia. Mol. Psychiatry10,589–597 (2005).
Medline CASGoogle Scholar
26 Nackley AG, Shabalina SA, Tchivileva IE et al.: Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science314,1930–1933 (2006).▪▪ Study highlighted the functional significance of synonymous variations and suggested the importance of haplotypes over SNPs for analysis of genetic variations.
Medline CASGoogle Scholar
27 DeMille MM, Kidd JR, Ruggeri V et al.: Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation. Hum. Genet.111,521–537 (2002).
Medline CASGoogle Scholar
28 Mukherjee N, Kidd KK, Pakstis AJ et al.: The complex global pattern of genetic variation and linkage disequilibrium at catechol-O-methyltransferase. Mol. Psychiatry (2008) (Epub ahead of print).▪ Study provides a common reference data set of genetic variations and haplotypes across the COMT gene and flanking regions in 45 populations.
MedlineGoogle Scholar
29 Wing JK, Babor T, Brugha T et al.: SCAN. Schedules for clinical assessment in neuropsychiatry. Arch. Gen. Psychiatry47,589–593 (1990).
Medline CASGoogle Scholar
30 McGuffin P, Farmer A, Harvey I: A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Arch. Gen. Psychiatry48,764–770 (1991).
Medline CASGoogle Scholar
31 Guy W: Clinical Global Impressions. In: ECDEU Assessment Manual for Psychopharmacology, revised (DHEW Publ No ADM 76–338). National Institute of Mental Health: Rockville, MD, USA, 218–222 (1976).
Google Scholar
32 Kukreti R, Tripathi S, Bhatnagar P et al.: Association of DRD2 gene variant with schizophrenia. Neurosci. Lett.392,68–71 (2006).
Medline CASGoogle Scholar
33 Gupta M, Chauhan C, Bhatnagar P et al.: Genetic susceptibility to schizophrenia: role of dopaminergic pathway gene polymorphisms. Pharmacogenomics10(2),277–291 (2009).
CASGoogle Scholar
34 Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res.16,1215 (1988).
Medline CASGoogle Scholar
35 Pritchard JK, Rosenberg NA: Use of unlinked genetic markers to detect population stratification in association studies. Am. J. Hum. Genet.65,220–228 (1999).
Medline CASGoogle Scholar
36 Gordon D, Finch SJ, Nothnagel M, Ott J: Power and sample size calculations for case–control genetic association tests when errors are present: application to single nucleotide polymorphisms. Hum. Hered.54,22–33 (2002).
MedlineGoogle Scholar
37 Gordon D, Levenstien MA, Finch SJ, Ott J: Errors and linkage disequilibrium interact multiplicatively when computing sample sizes for genetic case–control association studies. Pac. Symp. Biocomput.490–501 (2003).
MedlineGoogle Scholar
38 Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics21,263–265 (2005).
Medline CASGoogle Scholar
39 Excoffier L, Laval G, Schneider S: Arlequin (version 3.1): An integrated Software Package for Population Genetics Data Analysis. Computational and Molecular Population Genetics Lab (CMPG), Institute of Zoology, University of Berne, Switzerland (2006).
Google Scholar
40 Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet.68,978–989 (2001).
Medline CASGoogle Scholar
41 Stephens M, Donnelly P: A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am. J. Hum. Genet.73,1162–1169 (2003).
Medline CASGoogle Scholar
42 Sham PC, Curtis D: Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann. Hum. Genet.59,97–105 (1995).
Medline CASGoogle Scholar
43 Verma R, Chauhan C, Saleem Q et al.: A nonsense mutation in the synaptogyrin 1 gene in a family with schizophrenia. Biol. Psychiatry.55,196–199 (2004).
Medline CASGoogle Scholar
44 Verma R, Mukerji M, Grover D et al.: MLC1 gene is associated with schizophrenia and bipolar disorder in southern India. Biol. Psychiatry58,16–22 (2005).
Medline CASGoogle Scholar
45 Verma R, Kubendran S, Das SK, Jain S, Brahmachari SK: SYNGR1 is associated with schizophrenia and bipolar disorder in southern India. J. Hum. Genet.50,635–640 (2005).
Medline CASGoogle Scholar
46 Gupta S, Jain S, Brahmachari SK, Kukreti R: Pharmacogenomics: a path to predictive medicine for schizophrenia. Pharmacogenomics7,31–47 (2006).▪▪ Comprehensive review which presents a network model of the interaction between the neurotransmitter signaling systems.
CASGoogle Scholar
47 Meyer-Lindenberg A, Nichols T, Callicott JH et al.: Impact of complex genetic variation in COMT on human brain function. Mol. Psychiatry11,867–877 (2006).
Medline CASGoogle Scholar
48 Lin PI, Vance JM, Pericak-Vance MA, Martin ER: No gene is an island: the flip–flop phenomenon. Am. J. Hum. Genet.80,531–538 (2007).
Medline CASGoogle Scholar
49 Shibata K, Diatchenko L, Zaykin DV: Haplotype associations with quantitative traits in the presence of complex multilocus and heterogeneous effects. Genet. Epidemiol.33(1),63–78 (2008).
MedlineGoogle Scholar
50 Bertolino A, Caforio G, Blasi G et al.: Interaction of COMT Val108/158Met genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am. J. Psychiatry161,1798–1805 (2004).
MedlineGoogle Scholar
101 Web resources for the OPCRIT package http://sgdp.iop.kcl.ac.uk/opcrit
Google Scholar
102 Website for dbSNP http://www.ncbi.nlm.nih.gov/projects/SNP/
Google Scholar

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

Bibliography

1 Saleem Q, Dash D, Gandhi C et al.: Association of CAG repeat loci on chromosome 22 with schizophrenia and bipolar disorder. Mol. Psychiatry6,694–700 (2001).
Medline CASGoogle Scholar
2 Shprintzen RJ, Goldberg R, Golding-Kushner KJ, Marion RW: Late-onset psychosis in the velo-cardio-facial syndrome. Am. J. Med. Genet.42,141–142 (1992).
Medline CASGoogle Scholar
3 Gothelf D, Schaer M, Eliez S: Genes, brain development and psychiatric phenotypes in velo-cardio-facial syndrome. Dev. Disabil. Res. Rev.14,59–68 (2008).
MedlineGoogle Scholar
4 Lotta T, Vidgren J, Tilgmann C et al.: Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry34,4202–4210 (1995).
Medline CASGoogle Scholar
5 Chen J, Lipska BK, Halim N et al.: Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am. J. Hum. Genet.75,807–821 (2004).
Medline CASGoogle Scholar
6 Palmatier MA, Kang AM, Kidd KK: Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol. Psychiatry46,557–567 (1999).▪ First global survey of frequency of COMT polymorphism (rs4680) undertaken in 30 diverse populations.
Medline CASGoogle Scholar
7 Chen X, Wang X, O’Neill AF, Walsh D, Kendler KS: Variants in the catechol-O-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families. Mol Psychiatry9,962–967 (2004).
Medline CASGoogle Scholar
8 Goghari VM, Sponheim SR: Differential association of the COMT Val158Met polymorphism with clinical phenotypes in schizophrenia and bipolar disorder. Schizophr. Res.103,186–191 (2008).
MedlineGoogle Scholar
9 Egan MF, Goldberg TE, Kolachana BS et al.: Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc. Natl Acad. Sci. USA98,6917–6922 (2001).
Medline CASGoogle Scholar
10 Woodward ND, Jayathilake K, Meltzer HY: COMT Val108/158Met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia. Schizophr. Res.90,86–96 (2007).
MedlineGoogle Scholar
11 Bilder RM, Volavka J, Lachman HM, Grace AA: The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology29,1943–1961 (2004).
Medline CASGoogle Scholar
12 Meyer-Lindenberg A, Kohn PD, Kolachana B et al.: Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat. Neurosci.8,594–596 (2005).
Medline CASGoogle Scholar
13 Tunbridge EM, Harrison PJ, Weinberger DR: Catechol-O-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol. Psychiatry60,141–151 (2006).
Medline CASGoogle Scholar
14 Semwal P, Prasad S, Varma PG, Bhagwat AM, Deshpande SN, Thelma BK: Candidate gene polymorphisms among North Indians and their association with schizophrenia in a case–control study. J. Genet.81,65–71 (2002).
Medline CASGoogle Scholar
15 Nunokawa A, Watanabe Y, Muratake T, Kaneko N, Koizumi M, Someya T: No associations exist between five functional polymorphisms in the catechol-O-methyltransferase gene and schizophrenia in a Japanese population. Neurosci. Res.58,291–296 (2007).
Medline CASGoogle Scholar
16 Fan JB, Zhang CS, Gu NF et al.: Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol. Psychiatry57,139–144 (2005).
Medline CASGoogle Scholar
17 Munafo MR, Bowes L, Clark TG, Flint J: Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies. Mol. Psychiatry10,765–770 (2005).
Medline CASGoogle Scholar
18 Illi A, Mattila KM, Kampman O et al.: Catechol-O-methyltransferase and monoamine oxidase A genotypes and drug response to conventional neuroleptics in schizophrenia. J. Clin. Psychopharmacol.23,429–434 (2003).
Medline CASGoogle Scholar
19 Illi A, Kampman O, Hänninen K et al.: Catechol-O-methyltransferase Val108/158Met genotype and response to antipsychotic medication in schizophrenia. Hum. Psychopharmacol.22,211–215 (2007).
Medline CASGoogle Scholar
20 Molero P, Ortuno F, Zalacain M, Patino-Garcia A: Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment. Pharmacogenomics J.7,418–426 (2007).
Medline CASGoogle Scholar
21 Yamanouchi Y, Iwata N, Suzuki T, Kitajima T, Ikeda M, Ozaki N: Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone. Pharmacogenomics J.3,356–361 (2003).
Medline CASGoogle Scholar
22 Nolan KA, Czobor P, Citrome LL et al.: Catechol-O-methyltransferase and monoamine oxidase-A polymorphisms and treatment response to typical and atypical neuroleptics. J. Clin. psychopharmacol.26,338–340 (2006).
MedlineGoogle Scholar
23 Chen ML, Chen CH: Chronic antipsychotics treatment regulates MAOA, MAOB and COMT gene expression in rat frontal cortex. J. Psychiatr. Res.41,57–62 (2007).▪ Study demonstrated that different antipsychotic drugs may differentially regulate the gene expression of COMT, which may partly account for the molecular mechanism of their different clinical efficacy.
MedlineGoogle Scholar
24 Shifman S, Bronstein M, Sternfeld M et al.: A highly significant association between a COMT haplotype and schizophrenia. Am. J. Hum. Genet.71,1296–1302 (2002).▪ Highly significant association of a COMT haplotype was reported in a large population.
Medline CASGoogle Scholar
25 Handoko HY, Nyholt DR, Hayward NK et al.: Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia. Mol. Psychiatry10,589–597 (2005).
Medline CASGoogle Scholar
26 Nackley AG, Shabalina SA, Tchivileva IE et al.: Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science314,1930–1933 (2006).▪▪ Study highlighted the functional significance of synonymous variations and suggested the importance of haplotypes over SNPs for analysis of genetic variations.
Medline CASGoogle Scholar
27 DeMille MM, Kidd JR, Ruggeri V et al.: Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation. Hum. Genet.111,521–537 (2002).
Medline CASGoogle Scholar
28 Mukherjee N, Kidd KK, Pakstis AJ et al.: The complex global pattern of genetic variation and linkage disequilibrium at catechol-O-methyltransferase. Mol. Psychiatry (2008) (Epub ahead of print).▪ Study provides a common reference data set of genetic variations and haplotypes across the COMT gene and flanking regions in 45 populations.
MedlineGoogle Scholar
29 Wing JK, Babor T, Brugha T et al.: SCAN. Schedules for clinical assessment in neuropsychiatry. Arch. Gen. Psychiatry47,589–593 (1990).
Medline CASGoogle Scholar
30 McGuffin P, Farmer A, Harvey I: A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Arch. Gen. Psychiatry48,764–770 (1991).
Medline CASGoogle Scholar
31 Guy W: Clinical Global Impressions. In: ECDEU Assessment Manual for Psychopharmacology, revised (DHEW Publ No ADM 76–338). National Institute of Mental Health: Rockville, MD, USA, 218–222 (1976).
Google Scholar
32 Kukreti R, Tripathi S, Bhatnagar P et al.: Association of DRD2 gene variant with schizophrenia. Neurosci. Lett.392,68–71 (2006).
Medline CASGoogle Scholar
33 Gupta M, Chauhan C, Bhatnagar P et al.: Genetic susceptibility to schizophrenia: role of dopaminergic pathway gene polymorphisms. Pharmacogenomics10(2),277–291 (2009).
CASGoogle Scholar
34 Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res.16,1215 (1988).
Medline CASGoogle Scholar
35 Pritchard JK, Rosenberg NA: Use of unlinked genetic markers to detect population stratification in association studies. Am. J. Hum. Genet.65,220–228 (1999).
Medline CASGoogle Scholar
36 Gordon D, Finch SJ, Nothnagel M, Ott J: Power and sample size calculations for case–control genetic association tests when errors are present: application to single nucleotide polymorphisms. Hum. Hered.54,22–33 (2002).
MedlineGoogle Scholar
37 Gordon D, Levenstien MA, Finch SJ, Ott J: Errors and linkage disequilibrium interact multiplicatively when computing sample sizes for genetic case–control association studies. Pac. Symp. Biocomput.490–501 (2003).
MedlineGoogle Scholar
38 Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics21,263–265 (2005).
Medline CASGoogle Scholar
39 Excoffier L, Laval G, Schneider S: Arlequin (version 3.1): An integrated Software Package for Population Genetics Data Analysis. Computational and Molecular Population Genetics Lab (CMPG), Institute of Zoology, University of Berne, Switzerland (2006).
Google Scholar
40 Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet.68,978–989 (2001).
Medline CASGoogle Scholar
41 Stephens M, Donnelly P: A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am. J. Hum. Genet.73,1162–1169 (2003).
Medline CASGoogle Scholar
42 Sham PC, Curtis D: Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann. Hum. Genet.59,97–105 (1995).
Medline CASGoogle Scholar
43 Verma R, Chauhan C, Saleem Q et al.: A nonsense mutation in the synaptogyrin 1 gene in a family with schizophrenia. Biol. Psychiatry.55,196–199 (2004).
Medline CASGoogle Scholar
44 Verma R, Mukerji M, Grover D et al.: MLC1 gene is associated with schizophrenia and bipolar disorder in southern India. Biol. Psychiatry58,16–22 (2005).
Medline CASGoogle Scholar
45 Verma R, Kubendran S, Das SK, Jain S, Brahmachari SK: SYNGR1 is associated with schizophrenia and bipolar disorder in southern India. J. Hum. Genet.50,635–640 (2005).
Medline CASGoogle Scholar
46 Gupta S, Jain S, Brahmachari SK, Kukreti R: Pharmacogenomics: a path to predictive medicine for schizophrenia. Pharmacogenomics7,31–47 (2006).▪▪ Comprehensive review which presents a network model of the interaction between the neurotransmitter signaling systems.
CASGoogle Scholar
47 Meyer-Lindenberg A, Nichols T, Callicott JH et al.: Impact of complex genetic variation in COMT on human brain function. Mol. Psychiatry11,867–877 (2006).
Medline CASGoogle Scholar
48 Lin PI, Vance JM, Pericak-Vance MA, Martin ER: No gene is an island: the flip–flop phenomenon. Am. J. Hum. Genet.80,531–538 (2007).
Medline CASGoogle Scholar
49 Shibata K, Diatchenko L, Zaykin DV: Haplotype associations with quantitative traits in the presence of complex multilocus and heterogeneous effects. Genet. Epidemiol.33(1),63–78 (2008).
MedlineGoogle Scholar
50 Bertolino A, Caforio G, Blasi G et al.: Interaction of COMT Val108/158Met genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am. J. Psychiatry161,1798–1805 (2004).
MedlineGoogle Scholar
101 Web resources for the OPCRIT package http://sgdp.iop.kcl.ac.uk/opcrit
Google Scholar
102 Website for dbSNP http://www.ncbi.nlm.nih.gov/projects/SNP/
Google Scholar

Vol. 10, No. 3

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Published online 16 March 2009

Published in print March 2009

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Acknowledgements

We thank the patients and family members for their participation. We are grateful to Professor Partha Mazumdar, Mitali Mukerji, Arijit Mukhopadhaya and Anurag Aggarwal for intellectual inputs; S Sharma and P Rana from TCGA facility for SNP genotyping.

Financial & conpeting interests disclosure

Financial support from Department of Biotechnology (DBT) and Council of Scientific and Industrial Research (CSIR) is duly acknowledged. MG and SG are grateful to CSIR for senior research fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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