| 1 | Arch. Gen. Psychiatry 2011 Mar 68: 232-40 |
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| PMID | 21383261 |
| Title | Common variants in the BCL9 gene conferring risk of schizophrenia. |
| Abstract | Recent genome-wide association studies have revealed that common variations and rare copy-number variations contribute to the risk of mental disorders. Rare recurrent microdeletions at 1q21.1 were reported to be associated with schizophrenia, and the BCL9 gene at 1q21.1 was also a functional candidate gene for mental disorders. To investigate and validate whether common variations exist in a functional candidate gene in the copy-number variation region, and, if so, to determine whether these variations confer risk of schizophrenia or other mental disorders. A 3-stage case-control study. Shanghai, China. A total of 12 229 subjects were included: 5772 normal controls, 4187 patients with schizophrenia, 1135 patients with bipolar disorder patients, and 1135 patients with major depressive disorder. Main Outcome Measure During the first and second stages of our study, we genotyped 10 single-nucleotide polymorphisms using the ligation detection reaction method. During the third stage of our study, all single-nucleotide polymorphisms were genotyped using TaqMan technology (Applied Biosystems, Foster City, California). During the first stage of our study, we found that rs672607 was significantly associated with schizophrenia (P = 2.69 × 10(-5)). During the second stage, rs672607 was successfully replicated (P = 1.33 × 10(-5)), and rs9326555 (P = .002), rs1240083 (P = 1.7 × 10(-4)), and rs688325 (P = .006) were newly identified to be significant. During the third stage, we genotyped all single-nucleotide polymorphisms in 1135 patients with schizophrenia, 1135 patients with bipolar disorder, 1135 patients with major depressive disorder, and 1135 normal controls for further validation. Finally, when we combined all the data from the 3 stages of our schizophrenia study, we found that rs9326555 (P = 1.53 × 10(-5)), rs10494251 (P = .02), rs1240083 (P = 1.52 × 10(-4)), rs672607 (P = 1.23 × 10(-11)), rs688325 (P = 2.54 × 10(-4)), and rs3766512 (P = .01) were significant. Moreover, we found that rs672607 was significant in major depressive disorder (P = .001) and bipolar disorder (P = .03), and rs10494251 (P = .04), rs1541187 (P = .04), rs688325 (P = .02), and rs946903 (P = .006) were significant in major depressive disorder. These findings indicate that common variations in the BCL9 gene confer risk of schizophrenia and may also be associated with bipolar disorder and major depressive disorder in the Chinese Han population. |
| SCZ Keywords | schizophrenia |
| 2 | PLoS ONE 2013 -1 8: e51674 |
| PMID | 23382809 |
| Title | BCL9 and C9orf5 are associated with negative symptoms in schizophrenia: meta-analysis of two genome-wide association studies. |
| Abstract | schizophrenia is a chronic and debilitating psychiatric condition affecting slightly more than 1% of the population worldwide and it is a multifactorial disorder with a high degree of heritability (80%) based on family and twin studies. Increasing lines of evidence suggest intermediate phenotypes/endophenotypes are more associated with causes of the disease and are less genetically complex than the broader disease spectrum. Negative symptoms in schizophrenia are attractive intermediate phenotypes based on their clinical and treatment response features. Therefore, our objective was to identify genetic variants underlying the negative symptoms of schizophrenia by analyzing two genome-wide association (GWA) data sets consisting of a total of 1,774 European-American patients and 2,726 controls. Logistic regression analysis of negative symptoms as a binary trait (adjusted for age and sex) was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 25 single nucleotide polymorphisms (SNPs) associated with negative symptoms with p<5×10(-5). Especially we detected five SNPs in the first two genes/loci strongly associated with negative symptoms of schizophrenia (P(meta-analysis)<6.22×10(-6)), which included three SNPs in the BCL9 gene: rs583583 showed the strongest association at a P(meta-analysis) of 6.00×10(-7) and two SNPs in the C9orf5 (the top SNP is rs643410 with a p = 1.29 ×10(-6)). Through meta-analysis, we identified several additional negative symptoms associated genes (ST3GAL1, RNF144, CTNNA3 and ZNF385D). This is the first report of the common variants influencing negative symptoms of schizophrenia. These results provide direct evidence of using of negative symptoms as an intermediate phenotype to dissect the complex genetics of schizophrenia. However, additional studies are warranted to examine the underlying mechanisms of these disease-associated SNPs in these genes. |
| SCZ Keywords | schizophrenia |
| 3 | Schizophr Bull 2014 Nov 40: 1285-99 |
| PMID | 24664977 |
| Title | Systematic prioritization and integrative analysis of copy number variations in schizophrenia reveal key schizophrenia susceptibility genes. |
| Abstract | schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and diagnostics. |
| SCZ Keywords | schizophrenia |
| 4 | Sci Rep 2015 -1 5: 15705 |
| PMID | 26494551 |
| Title | Association study of BCL9 gene polymorphism rs583583 with schizophrenia and negative symptoms in Japanese population. |
| Abstract | B-cell CLL/lymphoma 9 (BCL9) is located within the schizophrenia (SCZ) suspected locus chr1q21.1. A recent study reported that a single nucleotide polyphormism (SNP) within BCL9 (rs583583) is associated with negative symptoms of schizophrenia, as measured by the Positive and Negative Syndrome Scale (PANSS), in the Caucasian population. We therefore investigated genetic association of rs583583, and its effect on negative symptoms in the Japanese patients. For association analysis, we used a Japanese sample set comprising 1089 SCZ and 950 controls (CON). Analysis of the effect of rs586586 on negative symptoms as examined by PANSS was investigated using 280 SCZ. Furthermore, for analysis of cognitive performance, we investigated 90 SCZ and 51 CON using the Continuous Performance Test (CPT-IP) and the Wisconsin Card Sorting Test (WCST) Keio version. We did not detect association between rs583583 and SCZ. Furthermore, rs583583 was not associated with PANSS negative scores or with CPT-IT or WCST cognitive tests. Considering the results of our previous study, combined with the results of the current study of rs583583, we argue that BCL9 most likely does not harbor a common genetic variant that can increase the risk for SCZ in the Japanese population. |
| SCZ Keywords | schizophrenia |