| 1 | Brain Res. Mol. Brain Res. 2005 Jul 138: 70-83 |
|---|---|
| PMID | 15894402 |
| Title | CAT 53: a protein phosphatase 1 nuclear targeting subunit encoded in the MHC Class I region strongly expressed in regions of the brain involved in memory, learning, and Alzheimer's disease. |
| Abstract | We identified CAT 53 by cDNA hybridization selection as an expressed sequence tag (EST), located in the vicinity of HLA-C and designated as CAT (for HLA-C associated transcript) 53. CAT 53 encodes a protein described by others and commonly known as phosphatase 1 nuclear targeting subunit (PNUTS). PNUTS is a potent inhibitor of nuclear serine/threonine protein phosphatase 1 (PP1). We present the genomic organization of CAT 53, localize specific sites of mRNA transcription in thin sections of mouse brain by in-situ hybridization, and perform a structural analysis of the peptide domains. We also characterize the protein expression pattern for PNUTS by Western blotting and immunohistochemistry with PNUTS antibody in Alzheimer's disease (AD) brains and age-matched control brains. In-situ hybridization and immunohistochemistry analysis of human and mouse brain show high CAT 53 expression in the olfactory cortex, piriform cortex, and hippocampus. Very high expression of CAT 53 was found mainly in the hippocampus, frontal, and entorhinal cortex of control brains and in the neurofibrillary tangles of AD brain. In the hippocampus, CAT 53 is expressed in CA1 and CA3 cell layers and in the dentate gyrus. The hippocampus is known to play a fundamental role in learning and episodic memories and has been implicated in a number of neurological and psychiatric disorders, including AD, epilepsy, and schizophrenia. Our findings suggest that PNUTS, encoded by CAT 53 on 6p21.3, may have a role in the progression of AD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | J Clin Psychiatry 2011 Apr 72: 458-63 |
| PMID | 20868635 |
| Title | Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis. |
| Abstract | Clozapine is considered to be the most efficacious drug to treat schizophrenia, although it is underutilized, partially due to a side effect of agranulocytosis. This analysis of 74 candidate genes was designed to identify an association between sequence variants and clozapine-induced agranulocytosis (CIA). Blood and medical history were collected for 33 CIA cases and 54 clozapine-treated controls enrolled between April 2002 and December 2003. Significant markers from 4 genes were then assessed in an independently collected case-control cohort (49 CIA cases, 78 controls). Sequence variants in 5 genes were found to be associated with CIA in the first cohort: HLA-DQB1, HLA-C, DRD1, NTSR1, and CSF2RB. Sequence variants in HLA-DQB1 were also found to be associated with CIA in the second cohort. After refinement analyses of sequence variants in HLA-DQB1, a single SNP (single nucleotide polymorphism), 6672G>C, was found to be associated with risk for CIA; the odds of CIA are 16.9 times greater in patients who carry this marker compared to those who do not. A sequence variant (6672G>C) in HLA-DQB1 is associated with increased risk for CIA. This marker identifies a subset of patients with an exceptionally high risk of CIA, 1,175% higher than the overall clozapine-treated population under the current blood-monitoring system. Assessing risk for CIA by testing for this and other genetic variants yet to be determined may be clinically useful when deciding whether to begin or continue treatment with clozapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Biol. Psychiatry 2012 Oct 72: 620-8 |
| PMID | 22883433 |
| Title | Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia. |
| Abstract | We performed a genome-wide association study (GWAS) to identify common risk variants for schizophrenia. The discovery scan included 1606 patients and 1794 controls from Ireland, using 6,212,339 directly genotyped or imputed single nucleotide polymorphisms (SNPs). A subset of this sample (270 cases and 860 controls) was subsequently included in the Psychiatric GWAS Consortium-schizophrenia GWAS meta-analysis. One hundred eight SNPs were taken forward for replication in an independent sample of 13,195 cases and 31,021 control subjects. The most significant associations in discovery, corrected for genomic inflation, were (rs204999, p combined = 1.34 × 10(-9) and in combined samples (rs2523722 p combined = 2.88 × 10(-16)) mapped to the major histocompatibility complex (MHC) region. We imputed classical human leukocyte antigen (HLA) alleles at the locus; the most significant finding was with HLA-C*01:02. This association was distinct from the top SNP signal. The HLA alleles DRB1*03:01 and B*08:01 were protective, replicating a previous study. This study provides further support for involvement of MHC class I molecules in schizophrenia. We found evidence of association with previously reported risk alleles at the TCF4, VRK2, and ZNF804A loci. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Schizophr. Res. 2013 Jan 143: 11-7 |
| PMID | 23177929 |
| Title | Non-random mating, parent-of-origin, and maternal-fetal incompatibility effects in schizophrenia. |
| Abstract | Although the association of common genetic variation in the extended MHC region with schizophrenia is the most significant yet discovered, the MHC region is one of the more complex regions of the human genome, with unusually high gene density and long-range linkage disequilibrium. The statistical test on which the MHC association is based is a relatively simple, additive model which uses logistic regression of SNP genotypes to predict case-control status. However, it is plausible that more complex models underlie this association. Using a well-characterized sample of trios, we evaluated more complex models by looking for evidence for: (a) non-random mating for HLA alleles, schizophrenia risk profiles, and ancestry; (b) parent-of-origin effects for HLA alleles; and (c) maternal-fetal genotype incompatibility in the HLA. We found no evidence for non-random mating in the parents of individuals with schizophrenia in terms of MHC genotypes or schizophrenia risk profile scores. However, there was evidence of non-random mating that appeared mostly to be driven by ancestry. We did not detect over-transmission of HLA alleles to affected offspring via the general TDT test (without regard to parent of origin) or preferential transmission via paternal or maternal inheritance. We evaluated the hypothesis that maternal-fetal HLA incompatibility may increase risk for schizophrenia using eight classical HLA loci. The most significant alleles were in HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 but none was significant after accounting for multiple comparisons. We did not find evidence to support more complex models of gene action, but statistical power may have been limiting. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | J Psychiatr Res 2014 Mar 50: 73-8 |
| PMID | 24365204 |
| Title | Protein-interaction-network-based analysis for genome-wide association analysis of schizophrenia in Han Chinese population. |
| Abstract | schizophrenia is a severe neuropsychiatric disorder with a strong and complex genetic background. Recent genome-wide association studies (GWAS) have successfully identified several susceptibility loci of schizophrenia. In order to interpret the functional role of the genetic variants and detect the combined effects of some of these genes on schizophrenia, protein-interaction-network-based analysis (PINBA) has emerged as an effective approach. In the current study, we conducted a PINBA of our previous GWAS data taken from the Han Chinese population. In order to do so, we used dense module search (DMS), a method that locates densely connected modules for complex diseases by integrating the association signal from GWAS datasets into the human protein-protein interaction (PPI) network. As a result, we identified one gene set with a joint effect significantly associated with schizophrenia and gene expression profiling analysis suggested that they were mainly neuro- and immune-related genes, such as glutamatergic gene (GRM5), GABAergic genes (GABRB1, GABARAP) and genes located in the MHC region (HLA-C, TAP2, HIST1H1B). Further pathway enrichment analysis suggested that these genes are involved in processes related to neuronal and immune systems, such as the Adherens junction pathway, the Neurotrophin signaling pathway and the Toll-like receptor signaling pathway. In our study, we identified a set of susceptibility genes that had been missed in single-marker GWAS, and our findings could promote the study of the genetic mechanisms in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Psychiatry Res 2015 Aug 228: 945-9 |
| PMID | 26160200 |
| Title | Genes involved in pruning and inflammation are enriched in a large mega-sample of patients affected by Schizophrenia and Bipolar Disorder and controls. |
| Abstract | A molecular pathway analysis has been performed in order to complement previous genetic investigations on schizophrenia. 4486 schizophrenic patients and 4477 controls served as the investigation sample. 3521 Bipolar patients and 3195 controls served as replication sample. A molecular pathway associated with the neuronal pruning activity was found to be enriched in subjects with schizophrenia compared to controls. HLA-C and HLA-DRA had more SNPs associated with both schizophrenia and Bipolar Disorder than expected by chance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Psychiatry Res 2015 Aug 228: 945-9 |
| PMID | 26160200 |
| Title | Genes involved in pruning and inflammation are enriched in a large mega-sample of patients affected by Schizophrenia and Bipolar Disorder and controls. |
| Abstract | A molecular pathway analysis has been performed in order to complement previous genetic investigations on schizophrenia. 4486 schizophrenic patients and 4477 controls served as the investigation sample. 3521 Bipolar patients and 3195 controls served as replication sample. A molecular pathway associated with the neuronal pruning activity was found to be enriched in subjects with schizophrenia compared to controls. HLA-C and HLA-DRA had more SNPs associated with both schizophrenia and Bipolar Disorder than expected by chance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | PLoS ONE 2015 -1 10: e0144719 |
| PMID | 26674772 |
| Title | Evidence for Association of Cell Adhesion Molecules Pathway and NLGN1 Polymorphisms with Schizophrenia in Chinese Han Population. |
| Abstract | Multiple risk variants of schizophrenia have been identified by Genome-wide association studies (GWAS). As a complement for GWAS, previous pathway-based analysis has indicated that cell adhesion molecules (CAMs) pathway might be involved in the pathogenesis of schizophrenia. However, less replication studies have been reported. Our objective was to investigate the association between CAMs pathway and schizophrenia in the Chinese Han population. We first performed a pathway analysis utilizing our previous GWAS data. The CAMs pathway (hsa04514) was significantly associated with schizophrenia using hybrid gene set-based test (P = 1.03×10-10) and hypergeometric test (P = 5.04×10-6). Moreover, 12 genes (HLA-A, HLA-C, HLA-DOB, HLA-DPB1, HLA-DQA2, HLA-DRB1, MPZ, CD276, NLGN1, NRCAM, CLDN1 and ICAM3) were modestly significantly associated with schizophrenia (P<0.01). Then, we selected one promising gene neuroligin 1 (NLGN1) to further investigate the association between eight significant SNPs and schizophrenia in an independent sample (1814 schizophrenia cases and 1487 healthy controls). Our study showed that seven SNPs of NLGN1 and two haplotype blocks were significantly associated with schizophrenia. This association was confirmed by the results of combined analysis. Among them, SNP rs9835385 had the most significant association with schizophrenia (P = 2.83×10-7). Furthermore, in silico analysis we demonstrated that NLGN1 is preferentially expressed in human brain and SNP rs1488547 was related to the expression level. We validated the association of CAMs pathway with schizophrenia in pathway-level and identified one susceptibility gene NLGN1. Further investigation of the roles of CAMs pathway in the pathogenesis of schizophrenia is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |