Associations between DRDs and schizophrenia in a Korean population: multi-stage association analyses

The dysregulation of the dopaminergic system has been implicated in the pathophysiology of major psychosis, including schizophrenia, with dopamine receptor genes (DRDs) presently targeted as the most promising candidate genes. We investigated DRD1-5 for association with schizophrenia using a multi-stage approach in a Korean sample. One hundred forty-two SNPs in DRD1-5 were selected from the dbSNP, and the associations of each SNP were then screened and typed by MALDI-TOF mass spectrometry using pooled DNA samples from 150 patients with major psychosis and 150 controls. Each of the suggested SNPs was then genotyped and tested for an association within the individual samples comprising each pool. Finally, the positively associated SNPs were genotyped in an extended sample of 270 patients with schizophrenia and 350 controls. Among the 142 SNPs, 88 (62%) SNPs in our Korean population were polymorphic. At the pooling stage, 10 SNPs (DRD1: 2, DRD2: 3, and DRD4: 5) were identified (P < 0.05). SNPs rs1799914 of DRD1 (P = 0.046) and rs752306 of DRD4 (P = 0.017) had significantly different allele frequencies in the individually genotyped samples comprising the pool. In the final stage, with the extended sample, the suggestive association of DRD4 with rs752306 was lost, but the association of DRD1 with rs1799914 gained greater significance (P = 0.017). In these large-scale multi-stage analyses, we were able to find a possible association between DRD1 and schizophrenia. These findings suggested the potential contribution of a multi-step strategy for finding genes related to schizophrenia.

No Association of Functional Polymorphisms in Methlylenetetrahydrofolate Reductase and the Risk and Minor Physical Anomalies of Schizophrenia in Korean Population

Methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate metabolism, plays an important role in DNA methylation. It has been suggested that abnormal DNA methylation contributes to the pathogenesis of schizophrenia and congenital anomalies. The previous findings regarding the genetic relationship between MTHFR and schizophrenia are controversial. This study investigated the association of the two functional polymorphisms of MTHFR, C677T and A1298C, with the risk for schizophrenia. Furthermore, we conducted an updated meta-analysis on the two polymorphisms. In addition, we investigated the relationship between the polymorphisms and minor physical anomaly (MPA), which may represent neurodevelopmental aberrations in 201 schizophrenia patients and 350 normal control subjects. There was no significant association between either of the two polymorphisms and the risk of schizophrenia (chi-square = 0.001, df = 1, P = 0.971 for C677T; chi-square = 1.319, df = 1, P = 0.251 for A1298C). However, in meta-analysis, the C677T polymorphism showed a significant association in the combined and Asian populations (OR = 1.13, P = 0.005; OR = 1.21, P = 0.011, respectively) but not in the Korean and Caucasian populations alone. Neither polymorphism was associated with MPAs measured by the Waldrop scale (chi-square = 2.513, df = 2, P = 0.285). In conclusion, the present findings suggest that in the Korean population, the MTHFR polymorphisms are unlikely to be associated with the risk for schizophrenia and neurodevelopmental abnormalities related to schizophrenia.

Childhood Attention Deficit in the Patients with Bipolar Disorder and CHRNA7 Gene Polymorphisms / 대한정신약물학회지

OBJECTIVE: Patients with bipolar disorder have attention deficit during even euthymic status. Bipolar disorder patients showed more childhood attention deficit and other ADHD like feature. Alpha 7 nicotinic receptor (CHRNA7) gene has been known to play roles in attention and sensory gating, and association between CHRNA7 gene and bipolar disorder has been reported. Therefore, we investigated a possible association between childhood attention deficit of bipolar disorder and CHRNA7 gene polymorphisms. METHODS: We included 122 patients with bipolar disorder (89 subjects of bipolar disorder type I, 33 subjects of bipolar disorder type II). Childhood attention deficit was measured by Wender Utah Rating Scale (WURS). Factor analysis was done for WURS to extract inattention factor from childhood ADHD like feature. Three factors were extracted: Impulsivity, Inattention, and Mood instability. All subjects were ethnically Korean. Genotyping was done for three intronic Single Nucleotide Polymorphism (SNPs) of CHRNA7 gene: rs2337506 (A/G), rs6494223 (C/T), and rs12916879 (A/G). Analysis of association was done by UNPHASED version 3.1.4, a free software for genetic statistics. RESULTS: Genetic association tests found no association between factor score of inattention and any SNP or combination of SNPs of CHRNA7. Positive association between WURS total score and SNP rs6494223 (p=0.043), factor score of impulsivity and SNP rs2337506 (p=0.038) as well as SNP rs6494223 (p=0.043) was revealed. These positive associations were survived after 1,000 permutation tests. Combination of SNPs association tests performed for total WURS and factor scores could not find any significant association. CONCLUSION: We could not find association between CHRNA7 gene and childhood attention deficit in bipolar disorder. However, we found CHRNA7 gene involved in childhood impulsivity of bipolar disorder, another ADHD like feature. Further studies with larger sample and denser polymorphisms are necessary to clarify genetic role of CHRNA7 in attention and impulsivity of bipolar disorder.