| Schizophrenia, bipolar disorder and major depressive disorder are three common psychiatric diseases with high morbidity and heritability. Several lines of evidence indicate that schizophrenia, bipolar disorder and major depressive disorder have overlap in pathogenesis. To investigate and detect the sharing genetic factors of schizophrenia, bipolar disorder and major depressive disorder, we carried out association studies of the BCL9 gene and the MDGA1 gene respectively.The BCL9 gene locates at 1q21.1, which was reported to be associated with schizophrenia. BCL9 is required in the Wnt-stimulated signaling pathway, which influences neuroplasticity, cell survival and adult neurogenesis, and may be involved in the etiology of mental disorders. Therefore, the BCL9 gene was also a functional candidate gene for mental disorders. We chose ten tagSNPs to be genotyped. We carried out a 3-stage case-control study. Totally 12,229 Chinese Han subjects were included in this study: 5,772 normal control subjects, 4,187 schizophrenia patients, 1,135 bipolar disorder patients, and 1,135 major depressive disorder patients. In the 1st and 2nd stage studies, we genotyped all ten tagSNPs using the Ligation Detection Reaction method （LDR）. In the 3rd stage study, all tagSNPs were genotyped on the ABI 7900 DNA detection system using TaqMan? technology. In the 1st stage study, we found that rs672607 was significantly associated with schizophrenia (p=2.69×10-5). Then in the 2nd stage study, rs672607 was successfully replicated (p=1.33×10-5), and rs9326555 （p=0.0015）, rs1240083 (p=1.7×10-4), and rs688325 （p=0.006） were newly identified to be significant. We conducted the 3rd stage study by genotyping all tagSNPs in 1,135 schizophrenia patients, 1,135 bipolar disorder patients, 1,135 major depressive disorder patients and 1,135 shared normal controls for further validation. Finally, in the combined schizophrenia study, rs9326555 (p=1.53×10-5), rs10494251 （p=0.018）, rs1240083 (p=1.52×10-4), rs672607 (p=1.23×10-11), rs688325 (p=2.54×10-4), and rs3766512 （p=0.0098） were significant. Moreover, we also found that rs672607 was significant in major depressive disorder （p=0.001） and bipolar disorder （p=0.031）, and rs10494251 （p=0.036）, rs1541187 （p=0.039）, rs688325 （p=0.015）, and rs946903 （p=0.006） were significant in major depressive disorder in the 3rd stage study. In addition, we carried out population stratification analysis in the 3rd stage sample set. We found that there was no obvious population stratification in our subjects, and our results should not be false positive association simply caused by population stratification. The structural, cytoarchitectural and functional brain abnormalitities reported in patients with mental disorders may be due to aberrant neuronal migration influenced by cell adhesion molecules. MDGA1, like Ig-containing cell adhesion molecules, has several cell adhesion molecule-like domains. Moreover, Kahler et al. reported that the MDGA1 gene was a schizophrenia susceptibility gene in Scandinavian population. We recruited 1,135 schizophrenia patients, 1,135 bipolar disorder patients, 1,135 major depressive disorder patients and 1,135 normal control subjects of Chinese Han origin. A total of 11 common SNPs were genotyped using TaqMan? technology. The genotype frequency of rs11759115 differed significantly between schizophrenia patients and controls （permutated p=0.0086）. Haplotype analysis revealed that the C-C haplotype consisting of rs11759115 and rs7769372 was positively associated with schizophrenia （permutated p=0.046）. Rs1883901 was found to be positively associated with bipolar disorder in both allele and genotype distribution （allele: permutated p=0.0085; genotype: permutated p=0.0009; OR=1.31 [95%CI=1.12-1.52]）. A haplotype consisting of rs1883901, rs10807187 and rs9462343 was positively associated with bipolar disorder with a global p value of 0.0391 after permutations. After permutations, the p value of an A-G-G haplotype of rs1883901- rs10807187-rs9462343 was 0.017. No individual SNP or haplotype was associated with major depressive disorder. In Conclusion, these results indicate that common variants in the BCL9 gene confer risk to schizophrenia, bipolar disorder and major depressive disorder in Chinese Han population and the MDGA1 gene confers risk to bipolar disorder and schizophrenia in the Chinese Han population. These findings will provide some help for the research of mental disorders pathogenesis. |
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