1BMC Genet. 2006 -1 7: 34
PMID16749937
TitleAssociation study of the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia.
AbstractBrahma (BRM) is a key component of the multisubunit SWI/SNF complex, a complex which uses the energy of ATP hydrolysis to remodel chromatin. BRM contains an N-terminal polyglutamine domain, encoded by a polymorphic trinucleotide (CAA/CAG) repeat, the only known polymorphism in the coding region of the gene (SMARCA2). We have examined the association of this polymorphism with schizophrenia in a family-based and case/control study. SMARCA2 was chosen as a candidate gene because of its specific role in developmental pathways, its high expression level in the brain and some evidence of its association with schizophrenia spectrum disorder from genome-wide linkage analysis.
Family-based analysis with 281 complete and incomplete triads showed that there is no significant preferential transmission of any of the alleles to the affected offspring. Also, in the case/control analysis, similar allele and genotype distributions were observed between affected cases (n = 289) and unaffected controls (n = 273) in each of three Caucasian populations studied: French Canadian, Tunisian and other Caucasians of European origin.
Results from our family-based and case-control association study suggest that there is no association between the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
2Hum. Mol. Genet. 2009 Jul 18: 2483-94
PMID19363039
TitleInvolvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia.
AbstractChromatin remodeling may play a role in the neurobiology of schizophrenia and the process, therefore, may be considered as a therapeutic target. The SMARCA2 gene encodes BRM in the SWI/SNF chromatin-remodeling complex, and associations of single nucleotide polymorphisms (SNPs) to schizophrenia were found in two linkage disequilibrium blocks in the SMARCA2 gene after screening of 11 883 SNPs (rs2296212; overall allelic P = 5.8 x 10(-5)) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490; overall allelic P = 2.0 x 10(-6)) in a Japanese population. A risk allele of a missense polymorphism (rs2296212) induced a lower nuclear localization efficiency of BRM, and risk alleles of intronic polymorphisms (rs3763627 and rs3793490) were associated with low SMARCA2 expression levels in the postmortem prefrontal cortex. A significant correlation in the fold changes of gene expression from schizophrenic prefrontal cortex (from the Stanley Medical Research Institute online genomics database) was seen with suppression of SMARCA2 in transfected human cells by specific siRNA, and of orthologous genes in the prefrontal cortex of SMARCA2 knockout mice. SMARCA2 knockout mice showed impaired social interaction and prepulse inhibition. Psychotogenic drugs lowered SMARCA2 expression while antipsychotic drugs increased it in the mouse brain. These findings support the existence of a role for BRM in the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
3Hum. Mol. Genet. 2009 Jul 18: 2483-94
PMID19363039
TitleInvolvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia.
AbstractChromatin remodeling may play a role in the neurobiology of schizophrenia and the process, therefore, may be considered as a therapeutic target. The SMARCA2 gene encodes BRM in the SWI/SNF chromatin-remodeling complex, and associations of single nucleotide polymorphisms (SNPs) to schizophrenia were found in two linkage disequilibrium blocks in the SMARCA2 gene after screening of 11 883 SNPs (rs2296212; overall allelic P = 5.8 x 10(-5)) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490; overall allelic P = 2.0 x 10(-6)) in a Japanese population. A risk allele of a missense polymorphism (rs2296212) induced a lower nuclear localization efficiency of BRM, and risk alleles of intronic polymorphisms (rs3763627 and rs3793490) were associated with low SMARCA2 expression levels in the postmortem prefrontal cortex. A significant correlation in the fold changes of gene expression from schizophrenic prefrontal cortex (from the Stanley Medical Research Institute online genomics database) was seen with suppression of SMARCA2 in transfected human cells by specific siRNA, and of orthologous genes in the prefrontal cortex of SMARCA2 knockout mice. SMARCA2 knockout mice showed impaired social interaction and prepulse inhibition. Psychotogenic drugs lowered SMARCA2 expression while antipsychotic drugs increased it in the mouse brain. These findings support the existence of a role for BRM in the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
4Hum. Mol. Genet. 2010 Jul 19: 2841-57
PMID20457675
TitleSMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution.
AbstractThe SMARCA2 gene, which encodes BRM in the SWI/SNF chromatin-remodeling complex, was recently identified as being associated with schizophrenia (SZ) in a genome-wide approach. Polymorphisms in SMARCA2, associated with the disease, produce changes in the expression of the gene and/or in the encoded amino acid sequence. We show here that an SWI/SNF-centered network including the SMARCA2 gene is modified by the down-regulation of REST/NRSF in a mouse neuronal cell line. REST/NRSF down-regulation also modifies the levels of Smarce1, Smarcd3 and SWI/SNF interactors (Hdac1, RcoR1 and Mecp2). SMARCA2 down-regulation generates an abnormal dendritic spine morphology that is an intermediate phenotype of SZ. We further found that 8 (CSF2RA, HIST1H2BJ, NOTCH4, NRGN, SHOX, SMARCA2, TCF4 and ZNF804A) out of 10 genome-wide supported SZ-associated genes are part of an interacting network (including SMARCA2), 5 members of which encode transcription regulators. The expression of 3 (TCF4, SMARCA2 and CSF2RA) of the 10 genome-wide supported SZ-associated genes is modified when the REST/NRSF-SWI/SNF chromatin-remodeling complex is experimentally manipulated in mouse cell lines and in transgenic mouse models. The REST/NRSF-SWI/SNF deregulation also results in the differential expression of genes that are clustered in chromosomes suggesting the induction of genome-wide epigenetic changes. Finally, we found that SMARCA2 interactors and the genome-wide supported SZ-associated genes are considerably enriched in genes displaying positive selection in primates and in the human lineage which suggests the occurrence of novel protein interactions in primates. Altogether, these data identify the SWI/SNF chromatin-remodeling complex as a key component of the genetic architecture of SZ.
SCZ Keywordsschizophrenia, schizophrenic
5J. Neurogenet. 2011 Oct 25: 88-103
PMID21797804
TitleDevelopment of patient-specific neurons in schizophrenia using induced pluripotent stem cells.
AbstractInduced pluripotent stem cell (iPSC) technology has the potential to transform regenerative medicine. It also offers a powerful tool for establishing in vitro models of disease, in particular, for neuropsychiatric disorders where live human neurons are essentially impossible to procure. Using iPSCs derived from three schizophrenia (SZ) patients, one of whom has 22q11.2del (velocardiofacial syndrome; VCFS), the authors developed a culture system to study SZ on a molecular and cellular level. SZ iPSCs were differentiated into functional, primarily glutamatergic neurons that were able to fire action potentials after ?8 weeks in culture. Early differentiating neurons expressed a number of transcription factors/chromatin remodeling proteins and synaptic proteins relevant to SZ pathogenesis, including ZNF804A, RELN, CNTNAP2, CTNNA2, SMARCA2, and NRXN1. Although a small number of lines were developed in this preliminary study, the SZ line containing 22q11.2del showed a significant delay in the reduction of endogenous OCT4 and NANOG expression that normally occurs during differentiation. Constitutive expression of OCT4 has been observed in Dgcr8-deficient mouse embryonic stem cells (mESCs); DGCR8 maps to the 22q11.2-deleted region. These findings demonstrate that the method of inducing neural differentiation employed is useful for disease modeling in SZ and that the transition of iPSCs with 22q11.2 deletions towards a differentiated state may be marked by subtle changes in expression of pluripotency-associated genes.
SCZ Keywordsschizophrenia, schizophrenic
6PLoS ONE 2014 -1 9: e94968
PMID24736721
TitleHeat shock alters the expression of schizophrenia and autism candidate genes in an induced pluripotent stem cell model of the human telencephalon.
Abstractschizophrenia (SZ) and autism spectrum disorders (ASD) are highly heritable neuropsychiatric disorders, although environmental factors, such as maternal immune activation (MIA), play a role as well. Cytokines mediate the effects of MIA on neurogenesis and behavior in animal models. However, MIA stimulators can also induce a febrile reaction, which could have independent effects on neurogenesis through heat shock (HS)-regulated cellular stress pathways. However, this has not been well-studied. To help understand the role of fever in MIA, we used a recently described model of human brain development in which induced pluripotent stem cells (iPSCs) differentiate into 3-dimensional neuronal aggregates that resemble a first trimester telencephalon. RNA-seq was carried out on aggregates that were heat shocked at 39C for 24 hours, along with their control partners maintained at 37C. 186 genes showed significant differences in expression following HS (p<0.05), including known HS-inducible genes, as expected, as well as those coding for NGFR and a number of SZ and ASD candidates, including SMARCA2, DPP10, ARNT2, AHI1 and ZNF804A. The degree to which the expression of these genes decrease or increase during HS is similar to that found in copy loss and copy gain copy number variants (CNVs), although the effects of HS are likely to be transient. The dramatic effect on the expression of some SZ and ASD genes places HS, and perhaps other cellular stressors, into a common conceptual framework with disease-causing genetic variants. The findings also suggest that some candidate genes that are assumed to have a relatively limited impact on SZ and ASD pathogenesis based on a small number of positive genetic findings, such as SMARCA2 and ARNT2, may in fact have a much more substantial role in these disorders - as targets of common environmental stressors.
SCZ Keywordsschizophrenia, schizophrenic