Studies On The Linkage Disequilibrium Of The Dopamine D3 Receptor Gene In Schizophrenia

Background and Objective: Schizophrenia is a group of clinical syndromes with unknown causation. Twin, family and adoption studies provide strong support for genetic factors in the pathogenesis of schizophrenia. Molecular genetics studies suggest that schizophrenia is a complex genetic disease caused by genes or together with environmental factors. Physiologic, pathologic and pharmacological evidences of several lines showed that the dysfunction of the human dopamine (DA) system may be implicated in the pathogenesis of schizophrenia. Many studies showed that the clinical effect of typical antipsychotic drugs for schizophrenia is due to their blockage of dopamine receptor (DR). The mRNA of the dopamine D3 receptor (DRD3) considered to be located in the limbic system of the brain is related to cognition and affection. The DRD3 may play a role in the control of thinking and emotion through DA system. Thus the DRD3 gene can be a good target in the DA system. The gene encoding DRD3 has been cloned and mapped to chromosome 3q13.3. A common polymorphism (Ser9Gly) has been described in exon 1 at the DRD3 gene. Though many studies have suggested that there may be an association between Ser9Gly and schizophrenia, few studies reported the relationship between the two polymorphisms (Ala38Thr and -205A/G) in the 5' region of the DRD3 gene and schizophrenia. Therefore, we studied the linkage disequilibrium of three polymorphisms in DRD3 gene in order to explore the relationship between schizophrenia and DRD3 gene in molecular genetics among Chinese Han nationality. Materials and Methods: Schizophrenia parent-offspring trios wereselected as research objects and investigated with self-editing family questionnaire according to Diagnostic Investigation Genet Scale (DIGS) provided by Harvard University. American diagnostic criterion DSM-IV (Diagnostic and Statistic Manual of Mental Disorder, 4th) and the Positive and Negative Syndrome Scale (PANSS) were employed, which is aimed to reach phenotypes consistency and reduce heterogeneity as possible. Genomic DNAs were isolated from the blood of 64 core pedigrees, 6 affected sib-pair pedigrees and 3 high-density family members of Chinese Han nationality, summed to 229 (including 88 schizophrenia patients) samples. Polymerase chain reaction (PCR) and restriction enzyme digestion were then performed. The association between the three polymorphism loci (Ser9Gly, Ala38Thr and -205A/G) in DRD3 gene and schizophrenia was analyzed by ( I ) investigation to schizophrenia parent-offspring trios combined with quantitative rating on phenotypes using standard review to the patients, (II) linkage disequilibrium study on the three polymorphism loci in DRD3 gene by using HHRR, Transmission Disequilibrium Test (TDT), (III) association analysis on the three polymorphism loci in DRJD3 gene among genotypes of schizophrenic patients, diagnosis isoforms and scores of PANSS factor.Results: (1) There were no significant differences between parent group and patient group from 73 integrity core pedigree members of Chinese Han nationality in genotype and allele gene frequency of the three polymorphism loci in DRD3 gene by case-parent control study (P>0.05). (2) The HHRR suggested that schizophrenia is associated with the polymorphism locus of -205A/G (x2=4.8388, P<0.05), but not of Ser9Gly or Ala38Thr (P>0.05). (3) The TDT of multiple allele did not show association between schizophrenia and these three polymorphism loci (P>0.05). (4) The multi-maker haplotypes analysis did not also reveal association between schizophrenia and haplotypes produced bythe three polymorphism loci (P>0.05). (5) There was no significant difference between genotypes of the three polymorphism loci and schizophrenic diagnosis isoforms among 88 schizophrenic patients. (6) The scores of depression factor showed significant difference among Ser9Ser group, Ser9Gly group and Gly9Gly group in 88 schizophrenia patients evaluated by PANSS (Positive and Negative Syndrome Scale) (P=0.042) . The score of depression factor of Gly9Gly group is...