| 1 | Genomics 2001 Apr 73: 123-6 |
|---|---|
| PMID | 11352574 |
| Title | Identification of genes from a schizophrenia-linked translocation breakpoint region. |
| Abstract | The translocation t(1:11)(q42.1,q14.3) has previously been found to be linked with schizophrenia. Genes present at the chromosome 1 breakpoint have been investigated in some detail but little was known about genes in the chromosome 11 breakpoint region. Here we report a BAC clone contig encompassing 2.51 Mb around the chromosome 11 breakpoint, which was constructed computationally using draft genomic sequence data and existing mapping data for the region. The contig includes 26 clones and has led to the identification and relative ordering of 10 candidate genes in the region, including 2 novel transcripts. It constitutes a resource for polymorphic marker discovery and association studies to validate or reject candidate genes. Four candidate genes appear to be particularly promising based upon their proximity to the breakpoint and their likely functional roles. Three of these are involved in glutamatergic neurotransmission (the glutamate receptor GRM5, NAALADase II, and a close homolog), perturbation of which is one of the most widely held theories on the underlying biochemistry of schizophrenia. The 4th gene, tyrosinase, has been previously linked to schizophrenia through the cosegregation of oculocutaneous albinism with psychosis in several pedigrees. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 2 | Mol. Psychiatry 2001 May 6: 311-4 |
| PMID | 11326300 |
| Title | The genomic organisation of the metabotropic glutamate receptor subtype 5 gene, and its association with schizophrenia. |
| Abstract | The G-protein coupled metabotropic glutamate receptors (GRMs/mGluRs) have been implicated in the aetiology of schizophrenia as they modulate the NMDA response and that of other neurotransmitters including dopamine and GABA.(1-3) Electrophysiological studies in GRM subtype 5 knockout mice reveal, in one study, a sensorimotor gating deficit characteristic of schizophrenia and in another, a key rôle for this gene in the modulation of hippocampal NMDA-dependent synaptic plasticity. In humans, GRM5 levels are increased in certain pyramidal cell neurons in schizophrenics vs controls.(6) Finally, GRM5 has been mapped to 11q14, neighbouring a translocation that segregates with schizophrenia and related psychoses in a large Scottish family, F23 (MLOD score 6.0). We determined the intron/exon structure of GRM5 and identified a novel intragenic microsatellite. A case-control association study identified a significant difference in allele frequency distribution between schizophrenics and controls (P = 0.04). This is suggestive of involvement of the GRM5 gene in schizophrenia in this population. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 3 | Mol. Psychiatry 2001 May 6: 311-4 |
| PMID | 11326300 |
| Title | The genomic organisation of the metabotropic glutamate receptor subtype 5 gene, and its association with schizophrenia. |
| Abstract | The G-protein coupled metabotropic glutamate receptors (GRMs/mGluRs) have been implicated in the aetiology of schizophrenia as they modulate the NMDA response and that of other neurotransmitters including dopamine and GABA.(1-3) Electrophysiological studies in GRM subtype 5 knockout mice reveal, in one study, a sensorimotor gating deficit characteristic of schizophrenia and in another, a key rôle for this gene in the modulation of hippocampal NMDA-dependent synaptic plasticity. In humans, GRM5 levels are increased in certain pyramidal cell neurons in schizophrenics vs controls.(6) Finally, GRM5 has been mapped to 11q14, neighbouring a translocation that segregates with schizophrenia and related psychoses in a large Scottish family, F23 (MLOD score 6.0). We determined the intron/exon structure of GRM5 and identified a novel intragenic microsatellite. A case-control association study identified a significant difference in allele frequency distribution between schizophrenics and controls (P = 0.04). This is suggestive of involvement of the GRM5 gene in schizophrenia in this population. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 4 | J Psychiatry Neurosci 2009 Nov 34: 450-8 |
| PMID | 19949721 |
| Title | Expression profiles of schizophrenia susceptibility genes during human prefrontal cortical development. |
| Abstract | Disruption in normal development of the human prefrontal cortex (PFC) may lead to cognitive dysfunction that manifests in individuals with schizophrenia. We sought to identify genes associated with age that are implicated in schizophrenia. We generated genome-wide expression profiles for the PFCs of humans ranging in age from 1 month to 49 years using the Affymetrix HG-U133 plus 2.0 microarrays (54 675 transcripts). Based on the criteria of significance (false discovery rate [FDR]-adjusted q < 0.001 and r(2) > 0.6), we identified the genes associated with age in the PFC. We then performed functional annotation analyses of age-associated genes using the Gene Ontology and the Genetic Association Database (GAD). We found robust age-dependent changes in gene expression in the PFCs of humans (2281 transcripts). The GAD analysis revealed that schizophrenia was an over-represented disease class, with 42 susceptibility genes included (p < 0.001, fold enrichment = 1.66, FDR = 1.5%). Among the 42 genes, glutamate receptor genes (GRIA1, GRIK1, GRIK2, GRIN2D, GRIP1, GRM5, GRM7 and SLC1A6) were consistently downregulated across age. We confirmed microarray gene expression changes by the quantitative polymerase chain reaction experiment. Although numerous genes undergo robust changes in expression during the PFC development, some of the changes may be confounded by known and unknown factors that are intrinsic to the postmortem brain studies. Multiple schizophrenia susceptibility genes undergo age-dependent expression changes in the human PFC, and any disruption in those genes during the critical period of development may predispose the individuals to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 5 | Mol. Psychiatry 2010 Jun 15: 637-46 |
| PMID | 19546859 |
| Title | Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. |
| Abstract | Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 6 | Front Genet 2013 -1 4: 58 |
| PMID | 23637704 |
| Title | Potential Impact of miR-137 and Its Targets in Schizophrenia. |
| Abstract | The significant impact of microRNAs (miRNAs) on disease pathology is becoming increasingly evident. These small non-coding RNAs have the ability to post-transcriptionally silence the expression of thousands of genes. Therefore, dysregulation of even a single miRNA could confer a large polygenic effect. schizophrenia is a genetically complex illness thought to involve multiple genes each contributing a small risk. Large genome-wide association studies identified miR-137, a miRNA shown to be involved in neuronal maturation, as one of the top risk genes. To assess the potential mechanism of impact of miR-137 in this disorder and identify its targets, we used a combination of literature searches, ingenuity pathway analysis (IPA), and freely accessible bioinformatics resources. Using TargetScan and the schizophrenia gene resource (SZGR) database, we found that in addition to CSMD1, C10orf26, CACNA1C, TCF4, and ZNF804A, five schizophrenia risk genes whose transcripts are also validated miR-137 targets, there are other schizophrenia-associated genes that may be targets of miR-137, including ERBB4, GABRA1, GRIN2A, GRM5, GSK3B, NRG2, and HTR2C. IPA analyses of all the potential targets identified several nervous system (NS) functions as the top canonical pathways including synaptic long-term potentiation, a process implicated in learning and memory mechanisms and recently shown to be altered in patients with schizophrenia. Among the subset of targets involved in NS development and function, the top scoring pathways were ephrin receptor signaling and axonal guidance, processes that are critical for proper circuitry formation and were shown to be disrupted in schizophrenia. These results suggest that miR-137 may indeed play a substantial role in the genetic etiology of schizophrenia by regulating networks involved in neural development and brain function. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 7 | Gene 2013 Feb 515: 163-6 |
| PMID | 23149219 |
| Title | Evaluation of hypermethylation and expression pattern of GMR2, GMR5, GMR8, and GRIA3 in patients with schizophrenia. |
| Abstract | Emerging evidence suggests a role of dysfunction of glutamatergic neurotransmission and its receptors in the pathophysiology of schizophrenia (SCZ). This study evaluated whether the promoter hypermethylation and RNA expression pattern of GMR2 (glutamate metabotropic receptor), GMR5, GMR8, and GRIA3 (glutamate receptor, ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) are associated with the risk of schizophrenia between schizophrenia patients and healthy controls. Methylation-specific polymerase chain reaction (MS-PCR) was used to estimate the promoter hypermethylation of GMR2, GMR5, GMR8, and GRIA3 genes on 81 isolated genomic DNA samples from the peripheral blood of individuals with schizophrenia and 71 healthy control subjects. In addition, real-time reverse transcription-PCR was used to estimate mRNA levels in 34 blood samples of healthy controls and cases. The methylation of GRM2 and GRM5 greatly decreased the risk of schizophrenia in comparison to the reference unmethylated pattern [OR=0.38, 95% CI; 0.144-1.035, p=0.05; OR=0.06, 95% CI; 0.007-0.54.10, p=0.01], respectively. The methylation of GRIA3 highly increased the risk of schizophrenia, but non-significant (OR=2.3, 95% CI; 0.51-10.42). The outcomes of the expression analysis revealed a statistically significant difference between the cases (n=17) and healthy controls (n=17) regarding the relative gene expression of GRM2, GRM5, and GRIA3 (p=0.0001). To the best of our knowledge, this is the first evidence showing that the promoter methylation of the GMR2 and GMR5 genes greatly decreased the risk of schizophrenia, and the expression level of the GRM2, GRM5, and GRIA3 genes increased significantly in patients in comparison to healthy controls. These outcomes suggest that there is a need for more attention to be paid to the effect of epigenetic variations in the development of SCZ in further investigations. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 8 | JAMA Psychiatry 2013 Jun 70: 582-90 |
| PMID | 23553203 |
| Title | Support for the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia from exome sequencing in multiplex families. |
| Abstract | schizophrenia is a complex genetic disorder demonstrating considerable heritability. Genetic studies have implicated many different genes and pathways, but much of the genetic liability remains unaccounted for. Investigation of genetic forms of schizophrenia will lead to a better understanding of the underlying molecular pathways, which will then enable targeted approaches for disease prevention and treatment. To identify new genetic factors strongly predisposing to schizophrenia in families with multiple affected individuals with schizophrenia. We performed genome-wide array comparative genomic hybridization, linkage analysis, and exome sequencing in multiplex families with schizophrenia. Probands and their family members were recruited from academic medical centers. We intended to identify rare disease-causing mutations in 5 large families where schizophrenia transmission appears consistent with single-gene inheritance. Array comparative genomic hybridization was used to identify copy number variants, while exome sequencing was used to identify variants shared in all affected individuals and linkage analysis was used to further filter shared variants of interest. Analysis of select variants was performed in cultured cells to assess their functional consequences. Rare inherited disease-related genetic mutations. No segregating rare copy number variants were detected by array comparative genomic hybridization. However, in all 5 families, exome sequencing detected rare protein-altering variants in 1 of 3 genes associated with the N -methyl-D-aspartate (NMDA) receptor. One pedigree shared a missense and frameshift substitution of GRM5, encoding the metabotropic glutamate receptor subtype 5 (mGluR5), which is coupled to the NMDA receptor and potentiates its signaling; the frameshift disrupts binding to the scaffolding protein tamalin and increases mGluR5 internalization. Another pedigree transmitted a missense substitution in PPEF2, encoding a calmodulin-binding protein phosphatase, which we show influences mGluR5 levels. Three pedigrees demonstrated different missense substitutions within LRP1B, encoding a low-density lipoprotein receptor-related protein tied to both the NMDA receptor and located in a chromosome 2q22 region previously strongly linked to schizophrenia. Exome sequencing of multiplex pedigrees uncovers new genes associated with risk for developing schizophrenia and suggests potential novel therapeutic targets. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 9 | Ann. Neurol. 2014 Jul 76: 82-94 |
| PMID | 24853231 |
| Title | Seroprevalence of autoantibodies against brain antigens in health and disease. |
| Abstract | We previously reported an unexpectedly high seroprevalence (~10%) of N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1) autoantibodies (AB) in healthy and neuropsychiatrically ill subjects (N = 2,817). This finding challenges an unambiguous causal relationship of serum AB with brain disease. To test whether similar results would be obtained for other brain antigen-directed AB previously connected with pathological conditions, we systematically screened serum samples of 4,236 individuals. Serum samples of healthy (n = 1,703) versus neuropsychiatrically ill subjects (schizophrenia, affective disorders, stroke, Parkinson disease, amyotrophic lateral sclerosis, personality disorder; total n = 2,533) were tested. For analysis based on indirect immunofluorescence, we used biochip mosaics of frozen brain sections (rat, monkey) and transfected HEK293 cells expressing respective recombinant target antigens. Seroprevalence of all screened AB was comparable in healthy and ill individuals. None of them, however, reached the abundance of NMDAR1 AB (again ~10%; immunoglobulin [Ig] G ~1%). Appreciable frequency was noted for AB against amphiphysin (2.0%), ARHGAP26 (1.3%), CASPR2 (0.9%), MOG (0.8%), GAD65 (0.5%), Ma2 (0.5%), Yo (0.4%), and Ma1 (0.4%), with titers and Ig class distribution similar among groups. All other AB were found in ?0.1% of individuals (anti-AMPAR-1/2, AQP4, CV2, Tr/DNER, DPPX-IF1, GABAR-B1/B2, GAD67, GLRA1b, GRM1, GRM5, Hu, LGl1, recoverin, Ri, ZIC4). The predominant Ig class depended on antigen location, with intracellular epitopes predisposing to IgG (chi-square = 218.91, p = 2.8 × 10(-48) ). To conclude, the brain antigen-directed AB tested here are comparably detectable in healthy subjects and the disease groups studied here, thus questioning an upfront pathological role of these serum AB. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 10 | 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, schizophrenics |
| 11 | Neuropharmacology 2015 Sep -1: -1 |
| PMID | 26349010 |
| Title | Shifting towards a model of mGluR5 dysregulation in schizophrenia: Consequences for future schizophrenia treatment. |
| Abstract | Metabotropic glutamate receptor subtype 5 (mGluR5), encoded by the GRM5 gene, represents a compelling novel drug target for the treatment of schizophrenia. mGluR5 is a postsynaptic G-protein coupled glutamate receptor strongly linked with several critical cellular processes that are reported to be disrupted in schizophrenia. Accordingly, mGluR5 positive allosteric modulators show encouraging therapeutic potential in preclinical schizophrenia models, particularly for the treatment of cognitive dysfunctions against which currently available therapeutics are largely ineffective. More work is required to support the progression of mGluR5-targeting drugs into the clinic for schizophrenia treatment, although some obstacles may be overcome by comprehensively understanding how mGluR5 itself is involved in the neurobiology of the disorder. Several processes that are necessary for the regulation of mGluR5 activity have been identified, but not examined, in the context of schizophrenia. These processes include protein-protein interactions, dimerisation, subcellular trafficking, the impact of genetic variability or mutations on protein function, as well as epigenetic, post-transcriptional and post-translational processes. It is essential to understand these aspects of mGluR5 to determine whether they are affected in schizophrenia pathology, and to assess the consequences of mGluR5 dysfunction for the future use of mGluR5-based drugs. Here, we summarise the known processes that regulate mGluR5 and those that have already been studied in schizophrenia, and discuss the consequences of this dysregulation for current mGluR5 pharmacological strategies. |
| SCZ Keywords | schizophrenia, schizophrenics |