常见精神疾病共享遗传风险研究
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摘要
精神分裂症、双相情感障碍和重性抑郁症是三种常见的精神疾病,发病率较高。大量研究显示这三种疾病在发病机制方面存在交叉重叠。为了寻找精神分裂症、双相情感障碍和重性抑郁症的共享遗传风险因子,我们分别开展了BCL9基因和MDGA1基因与这三种精神疾病的关联分析。
BCL9基因位于染色体1q21.1的位置,该位置被证实和精神分裂症相关。此外,BCL9是Wnt信号通路中重要的一员,该通路在神经发育过程中起着重要的作用,因此BCL9基因还是精神疾病研究的功能候选基因。为了验证BCL9基因在中国汉族人群中是否是精神分裂症、双相情感障碍和重性抑郁症的共享遗传风险因子,我们对10个tagSNPs在12,229个样本(包括5,772个正常对照样本、4,187个精神分裂症患者、1,135个双相情感障碍患者和1,135个重性抑郁症患者)中进行分型。实验由三步组成,第一步和第二步采用LDR基因分型技术,第三步采用Taqman基因分型技术。在第一步实验中,我们发现rs672607与精神分裂症显著性相关(p=2.69×10~(-5))。在第二步试验中,我们成功重复到rs672607 (p=1.33×10~(-5))与精神分裂症显著性相关,另外我们还发现rs9326555、rs1240083和rs688325也与精神分裂症显著性相关(rs9326555 (p=0.0015) ; rs1240083(p=1.7×10~(-4));rs688325 (p=0.006))。第三步实验样本由1,135个精神分裂症患者、1,135个双相情感障碍患者、1,135个重性抑郁症患者和1,135个正常对照样本组成,我们再次验证rs672607与精神分裂症显著性相关,另外,还发现rs672607 (p=0.031)与双相情感障碍相关,rs672607、rs10494251、rs1541187、rs688325和rs946903与重性抑郁症相关(rs672607 (p=0.001);rs10494251 (p=0.036); rs1541187 (p=0.039);rs688325 (p=0.015);rs946903 (p=0.006))。最后我们将有关精神分裂症的三步研究进行合并,发现rs9326555、rs10494251、rs1240083、rs672607、rs688325和rs3766512 (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)); rs3766512 (p=0.0098))与精神分裂症显著性相关。此外,我们还对第三步实验样本进行了人群层化分析,排除了由于人群层化导致的假阳性的问题。
大量研究发现由细胞粘附分子介导的神经元迁移的异常会导致精神病患者的脑以及细胞结构的异常。像很多细胞粘附分子一样,MDGA1也包含很多起细胞粘附作用的结构域。此外,有文献报道MDGA1基因在高加索人群中与精神分裂症有显著性相关。为了进一步验证MDGA1基因在中国汉族人群中是否也与精神分裂症、双相情感障碍和重性抑郁症相关,我们对11个SNPs在1,135个精神分裂症患者、1,135个双相情感障碍患者、1,135个重性抑郁症患者和1,135个正常对照样本进行Taqman基因分型。我们发现rs11759115、rs1883901和rs9462341与精神分裂症有显著性关联(rs11759115, allele: p=0.01, genotype: p=0.003,odds ratio (OR)=0.81[0.68-0.96]; rs1883901, allele: p=0.02,genotype: p=0.02, OR=1.19 [1.0-1.39]; rs9462341, allele: p=0.03, genotype: p=0.02, OR=0.87 [=0.77-0.98])。经矫正后,rs11759115仍然与精神分裂症显著性相关(p=0.009)。由rs11759115和rs7769372组成的单倍型C-C与精神分裂症相关。对于双相情感障碍,我们发现rs1883901与双相情感障碍显著性相关(allele: p=0.0004, genotype: p=0.0004, OR=1.31 [1.12-1.52])。经矫正后,rs1883901仍然具有显著性(allele: p=0.009; genotype: p=0.0009)。由rs1883901、rs10807187和rs9462343组成的单倍型A-G-G与双相情感障碍显著性关联。
总之,在本研究中,我们发现精神分裂症、双相情感障碍和重性抑郁症共享易感基因BCL9基因;精神分裂症和双相情感障碍共享易感基因MDGA1基因,为今后这三种常见精神疾病的发病机制研究和诊断治疗提供一定的依据。
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.
BCL9基因位于染色体1q21.1的位置,该位置被证实和精神分裂症相关。此外,BCL9是Wnt信号通路中重要的一员,该通路在神经发育过程中起着重要的作用,因此BCL9基因还是精神疾病研究的功能候选基因。为了验证BCL9基因在中国汉族人群中是否是精神分裂症、双相情感障碍和重性抑郁症的共享遗传风险因子,我们对10个tagSNPs在12,229个样本(包括5,772个正常对照样本、4,187个精神分裂症患者、1,135个双相情感障碍患者和1,135个重性抑郁症患者)中进行分型。实验由三步组成,第一步和第二步采用LDR基因分型技术,第三步采用Taqman基因分型技术。在第一步实验中,我们发现rs672607与精神分裂症显著性相关(p=2.69×10~(-5))。在第二步试验中,我们成功重复到rs672607 (p=1.33×10~(-5))与精神分裂症显著性相关,另外我们还发现rs9326555、rs1240083和rs688325也与精神分裂症显著性相关(rs9326555 (p=0.0015) ; rs1240083(p=1.7×10~(-4));rs688325 (p=0.006))。第三步实验样本由1,135个精神分裂症患者、1,135个双相情感障碍患者、1,135个重性抑郁症患者和1,135个正常对照样本组成,我们再次验证rs672607与精神分裂症显著性相关,另外,还发现rs672607 (p=0.031)与双相情感障碍相关,rs672607、rs10494251、rs1541187、rs688325和rs946903与重性抑郁症相关(rs672607 (p=0.001);rs10494251 (p=0.036); rs1541187 (p=0.039);rs688325 (p=0.015);rs946903 (p=0.006))。最后我们将有关精神分裂症的三步研究进行合并,发现rs9326555、rs10494251、rs1240083、rs672607、rs688325和rs3766512 (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)); rs3766512 (p=0.0098))与精神分裂症显著性相关。此外,我们还对第三步实验样本进行了人群层化分析,排除了由于人群层化导致的假阳性的问题。
大量研究发现由细胞粘附分子介导的神经元迁移的异常会导致精神病患者的脑以及细胞结构的异常。像很多细胞粘附分子一样,MDGA1也包含很多起细胞粘附作用的结构域。此外,有文献报道MDGA1基因在高加索人群中与精神分裂症有显著性相关。为了进一步验证MDGA1基因在中国汉族人群中是否也与精神分裂症、双相情感障碍和重性抑郁症相关,我们对11个SNPs在1,135个精神分裂症患者、1,135个双相情感障碍患者、1,135个重性抑郁症患者和1,135个正常对照样本进行Taqman基因分型。我们发现rs11759115、rs1883901和rs9462341与精神分裂症有显著性关联(rs11759115, allele: p=0.01, genotype: p=0.003,odds ratio (OR)=0.81[0.68-0.96]; rs1883901, allele: p=0.02,genotype: p=0.02, OR=1.19 [1.0-1.39]; rs9462341, allele: p=0.03, genotype: p=0.02, OR=0.87 [=0.77-0.98])。经矫正后,rs11759115仍然与精神分裂症显著性相关(p=0.009)。由rs11759115和rs7769372组成的单倍型C-C与精神分裂症相关。对于双相情感障碍,我们发现rs1883901与双相情感障碍显著性相关(allele: p=0.0004, genotype: p=0.0004, OR=1.31 [1.12-1.52])。经矫正后,rs1883901仍然具有显著性(allele: p=0.009; genotype: p=0.0009)。由rs1883901、rs10807187和rs9462343组成的单倍型A-G-G与双相情感障碍显著性关联。
总之,在本研究中,我们发现精神分裂症、双相情感障碍和重性抑郁症共享易感基因BCL9基因;精神分裂症和双相情感障碍共享易感基因MDGA1基因,为今后这三种常见精神疾病的发病机制研究和诊断治疗提供一定的依据。
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.
引文
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