Research Article
Genetic susceptibility to schizophrenia: role of dopaminergic pathway gene polymorphisms
Published Online:10 Feb 2009https://doi.org/10.2217/14622416.10.2.277
Abstract
Aim: We investigated 16 polymorphisms from three genes, dopamine receptor D2 (DRD2), catechol-O-methyl transferase (COMT) and brain derived neurotrophic factor (BDNF), which are involved in the dopaminergic pathways, and have been reported to be associated with susceptibility to schizophrenia and response to antipsychotic therapy. Materials & methods: Single-locus association analyses of these polymorphisms were carried out in 254 patients with schizophrenia and 225 controls, all of southern Indian origin. Additionally, multifactor-dimensionality reduction analysis was performed in 422 samples (243 cases and 179 controls) to examine the gene–gene interactions and to identify combinations of multilocus genotypes associated with either high or low risk for the disease. Results: Our results demonstrated initial significant associations of two SNPs for DRD2 (rs11608185, genotype: χ2 = 6.29, p-value = 0.043; rs6275, genotype: χ2 = 8.91, p-value = 0.011), and one SNP in the COMT gene (rs4680, genotype: χ2 = 6.67, p-value = 0.035 and allele: χ2 = 4.75, p-value = 0.029; odds ratio: 1.33, 95% confidence interval: 1.02–1.73), but not after correction for multiple comparisons indicating a weak association of individual markers of DRD2 and COMT with schizophrenia. Multifactor-dimensionality reduction analysis suggested a two locus model (rs6275/DRD2 and rs4680/COMT) as the best model for gene–gene interaction with 90% cross-validation consistency and 42.42% prediction error in predicting disease risk among schizophrenia patients. Conclusion: The present study thus emphasizes the need for multigene interaction studies in complex disorders such as schizophrenia and to understand response to drug treatment, which could lead to a targeted and more effective treatment.
Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest
Bibliography
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Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest
Bibliography
- 1 Muller DJ, Luca VD, Kennedy JL: Overview: towards individualized treatment in schizophrenia. Drug Dev. Res.60,75–94 (2003).
- 2 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).
- 3 Seeman P: Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse1,133–152 (1987).
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- 5 Arinami T, Gao M, Hamaguchi H, Toru M: A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum. Mol. Genet.6,577–582 (1997).
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- 7 Hanninen K, Katila H, Kampman O et al.: Association between the C957T polymorphism of the dopamine D2 receptor gene and schizophrenia. Neurosci. Lett.407,195–198 (2006).
- 8 Vijayan NN, Bhaskaran S, Koshy LV et al.: Association of dopamine receptor polymorphisms with schizophrenia and antipsychotic response in a South Indian population. Behav. Brain Funct.3,34 (2007).
- 9 Verga M, Macciardi F, Pedrini S, Cohen S, Smeraldi E: No association of the Ser/Cys311 DRD2 molecular variant with schizophrenia using a classical case control study and the haplotype relative risk. Schizophr. Res.25,117–121 (1997).
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- 17 Owen MJ, Williams NM, O’Donovan MC: The molecular genetics of schizophrenia: new findings promise new insights. Mol. Psychiatry9,14–27 (2004).
- 18 Williams NM, Owen MJ: Genetic abnormalities of chromosome 22 and the development of psychosis. Curr. Psychiatry Rep.6,176–182 (2004).
- 19 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).
- 20 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).
- 21 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).
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- 24 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).
- 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).
- 26 Abdolmaleky HM, Cheng KH, Faraone SV et al.: Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum. Mol. Genet.15,3132–3145 (2006).
- 27 Pelayo-Terán JM, Crespo-Facorro B, Carrasco-Marín E: Catechol-O-methyltransferase Val158Met polymorphism and clinical characteristics in first episode non-affective psychosis. Am. J. Med. Genet. B Neuropsychiatr. Genet.147B,550–556 (2008).
- 28 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).
- 29 Glatt SJ, Faraone SV, Tsuang MT: Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case–control and family-based studies. Am. J. Psychiatry160,469–476 (2003).
- 30 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).
- 31 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).
- 32 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).
- 33 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).▪ A highly significant association of COMT haplotype was reported in a large population.
- 34 Lee SG, Joo Y, Kim B et al.: Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans. Hum. Genet.116,319–328 (2005).
- 35 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).
- 36 Bray NJ, Buckland PR, Williams NM et al.: A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am. J. Hum. Genet.73,152–161 (2003).▪ The haplotype implicated in schizophrenia susceptibility was found to be associated with lower expression of COMT mRNA in human brain.
- 37 Angelucci F, Brene S, Mathe AA: BDNF in schizophrenia, depression and corresponding animal models. Mol. Psychiatry10,345–352 (2005).
- 38 Galderisi S, Maj M, Kirkpatrick B et al.: COMT Val(158)Met and BDNF C(270)T polymorphisms in schizophrenia: a case–control study. Schizophr. Res.73,27–30 (2005).
- 39 Dluzen DE, Gao X, Story GM, Anderson LI, Kucera J, Walro JM: Evaluation of nigrostriatal dopaminergic function in adult +/+ and +/- BDNF mutant mice. Exp. Neurol.170,121–128 (2001).
- 40 Durany N, Michel T, Zochling R et al.: Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses. Schizophr. Res.52,79–86 (2001).
- 41 Egan MF, Weinberger DR, Lu B: Schizophrenia, III: brain-derived neurotropic factor and genetic risk. Am. J. Psychiatry160,1242 (2003).
- 42 Neves-Pereira M, Cheung JK, Pasdar A et al.: BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol. Psychiatry10,208–212 (2005).
- 43 Watanabe Y, Muratake T, Kaneko N, Nunokawa A, Someya T: No association between the brain-derived neurotrophic factor gene and schizophrenia in a Japanese population. Schizophr. Res.84,29–35 (2006).
- 44 Naoe Y, Shinkai T, Hori H et al.: No association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and schizophrenia in Asian populations: Evidence from a case–control study and meta-analysis. Neurosci. Lett.415,108–112 (2007).
- 45 Cloninger CR: Multilocus genetics of schizophrenia. Curr. Opin. Psychiatry10,5–10 (1997).
- 46 Moore JH, Williams SM: New strategies for identifying gene–gene interactions in hypertension. Ann. Med.34,88–95 (2002).▪▪ A nonparametric and genetic model-free approach was adopted to develop a software for identifying gene–gene interactions.
- 47 Ritchie MD, Hahn LW, Roodi N et al.: Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am. J. Hum. Genet.69,138–147 (2001).▪ First report which demonstrated a four-locus interaction associated with a complex multifactorial disease in absence of any statistically significant independent main effects.
- 48 Cho YM, Ritchie MD, Moore JH et al.: Multifactor-dimensionality reduction shows a two-locus interaction associated with Type 2 diabetes mellitus. Diabetologia47,549–554 (2004).
- 49 Xu J, Lowey J, Wiklund F et al.: The interaction of four genes in the inflammation pathway significantly predicts prostate cancer risk. Cancer Epidemiol. Biomarkers Prev.14,2563–2568 (2005).
- 50 Motsinger AA, Brassat D, Caillier SJ et al.: Complex gene–gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes. Neurogenetics8,11–20 (2007).
- 51 Wing JK, Babor T, Brugha T et al.: SCAN. Schedules for clinical assessment in neuropsychiatry. Arch. Gen. Psychiatry47,589–593 (1990).
- 52 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).
- 53 Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res.16,1215 (1988).
- 54 Nyholt DR: A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am. J. Hum. Genet.74,765–769 (2004).
- 55 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).
- 56 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).
- 57 Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics21,263–265 (2005).
- 58 Hahn LW, Ritchie MD, Moore JH: Multifactor dimensionality reduction software for detecting gene–gene and gene–environment interactions. Bioinformatics19,376–382 (2003).
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