title: Genetic susceptibility to schizophrenia: role of dopaminergic pathway gene polymorphisms.
abstract: OBJECTIVE
  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.
  
  
  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: chi(2) = 6.29, p-value = 0.043; rs6275, genotype: chi(2) = 8.91, p-value = 0.011), and one SNP in the COMT gene (rs4680, genotype: chi(2) = 6.67, p-value = 0.035 and allele: chi(2) = 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Functional Genomics Unit, Institute of Genomics and Integrative Biology (Council of Scientific and Industrial Research), Mall Road, Delhi 110 007, India.
authors.forename: Meenal
authors.initials: M
authors.lastname: Gupta
authors.forename: Chitra
authors.initials: C
authors.lastname: Chauhan
authors.forename: Pallav
authors.initials: P
authors.lastname: Bhatnagar
authors.forename: Simone
authors.initials: S
authors.lastname: Gupta
authors.forename: Sandeep
authors.initials: S
authors.lastname: Grover
authors.forename: Prashant K
authors.initials: PK
authors.lastname: Singh
authors.forename: Meera
authors.initials: M
authors.lastname: Purushottam
authors.forename: Odity
authors.initials: O
authors.lastname: Mukherjee
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Jain
authors.forename: Samir K
authors.initials: SK
authors.lastname: Brahmachari
authors.forename: Ritushree
authors.initials: R
authors.lastname: Kukreti
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007194:India; D008297:Male; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D012016:Reference Values; D012559:Schizophrenia / Q000235:genetics*; D055815:Young Adult
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C493593:DRD3 protein, human; D050637:Receptors, Dopamine D3; D002394:Catechol O-Methyltransferase