| 1 | Psychiatry Res 2006 Jan 141: 39-51 |
|---|---|
| PMID | 16325263 |
| Title | Association study of polymorphisms in the GluR7, KA1 and KA2 kainate receptor genes (GRIK3, GRIK4, GRIK5) with schizophrenia. |
| Abstract | On the basis of the glutamatergic dysfunction hypothesis of schizophrenia, we have been conducting a systematic study of the association of glutamate receptor genes with schizophrenia. Here we report association studies of schizophrenia with polymorphisms in three kainate receptor genes: GRIK3, GRIK4 and GRIK5. We selected 16, 24 and 5 common single nucleotide polymorphisms (SNPs) distributed in the entire gene regions of GRIK3 (>240 kb), GRIK4 (>430 kb) and GRIK5 (>90 kb), respectively. We tested associations of the polymorphisms with schizophrenia using 100 Japanese case-control pairs (the Kyushu set). We observed no significant "single marker" associations with the disease in any of the 45 SNPs tested except for one (rs3767092) in GRIK3 showing a nominal level of significance. The significant association, however, disappeared after the application of the Bonferroni correction. We also observed significant haplotype associations in seven SNP pairs in GRIK3 and in four SNP pairs in GRIK4. None, however, remained significant after Bonferroni correction. We also failed to replicate the nominally significant haplotype associations in a second sample set, the Aichi set (106 cases and 100 controls). We conclude that SNPs in the gene regions of GRIK3, GRIK4 or GRIK5 do not play a major role in schizophrenia pathogenesis in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Mol. Psychiatry 2006 Sep 11: 847-57 |
| PMID | 16819533 |
| Title | Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. |
| Abstract | In the search for the biological causes of schizophrenia and bipolar disorder, glutamate neurotransmission has emerged as one of a number of candidate processes and pathways where underlying gene deficits may be present. The analysis of chromosomal rearrangements in individuals diagnosed with neuropsychiatric disorders is an established route to candidate gene identification in both Mendelian and complex disorders. Here we describe a set of genes disrupted by, or proximal to, chromosomal breakpoints (2p12, 2q31.3, 2q21.2, 11q23.3 and 11q24.2) in a patient where chronic schizophrenia coexists with mild learning disability (US: mental retardation). Of these disrupted genes, the most promising candidate is a member of the kainate-type ionotropic glutamate receptor family, GRIK4 (KA1). A subsequent systematic case-control association study on GRIK4 assessed its contribution to psychiatric illness in the karyotypically normal population. This identified two discrete regions of disease risk within the GRIK4 locus: three single single nucleotide polymorphism (SNP) markers with a corresponding underlying haplotype associated with susceptibility to schizophrenia (P=0.0005, odds ratio (OR) of 1.453, 95% CI 1.182-1.787) and two single SNP markers and a haplotype associated with a protective effect against bipolar disorder (P=0.0002, OR of 0.624, 95% CI 0.485-0.802). After permutation analysis to correct for multiple testing, schizophrenia and bipolar disorder haplotypes remained significant (P=0.0430, s.e. 0.0064 and P=0.0190, s.e. 0.0043, respectively). We propose that these convergent cytogenetic and genetic findings provide molecular evidence for common aetiologies for different psychiatric conditions and further support the 'glutamate hypothesis' of psychotic illness. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Neurotox Res 2007 Jan 11: 73-83 |
| PMID | 17449450 |
| Title | Are some genetic risk factors common to schizophrenia, bipolar disorder and depression? Evidence from DISC1, GRIK4 and NRG1. |
| Abstract | Depression is common in patients with schizophrenia and it is well established from family studies that rates of depression are increased among relatives of probands with schizophrenia, making it likely that the phenotypes described under the categories of affective and non-affective psychoses share some genetic risk factors. Family linkage studies have identified several chromosomal regions likely to contain risk genes for schizophrenia and bipolar disorder, suggesting common susceptibility loci. Candidate gene association studies have provided further evidence to suggest that some genes including two of the most studied candidates, Disrupted in schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) may be involved in both types of psychosis. We have recently identified another strong candidate for a role in both schizophrenia and affective disorders, GRIK4 a glutamate receptor mapped to chromosome 11q23 [Glutamate Receptor, Ionotropic, Kainate, type 4]. This gene is disrupted by a translocation breakpoint in a patient with schizophrenia, and case control studies show significant association of GRIK4 with both schizophrenia and bipolar disorder. Identifying genes implicated in the psychoses may eventually provide the basis for classification based on biology rather than symptoms, and suggest novel treatment strategies for these complex brain disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Neurotox Res 2008 Oct 14: 79-96 |
| PMID | 19073416 |
| Title | Schizopsychotic symptom-profiles and biomarkers: beacons in diagnostic labyrinths. |
| Abstract | Several avenues of investigation through which the 'labyrinths' of schizopsychotic diagnosis may be examined, are offered by the consideration of the 'beacons' of symptom-profiles and biomarkers. Neurodevelopmental issues and risk assessment, neurocognitive factors of predictive necessity, supersensitivity in neurotransmitter systems, the implications of prodromal expressions of the disorder, functional dysconnectivity arising from prefrontal to diverse regional patterns and circuits with a neurodevelopmental origin, and heritable gene characteristics are viewed against the backdrop of the schizophrenia spectrum disorders. The associations between adolescent-adult use of cannabis, on the one hand, and, alternatively, the prevalence of chromosomal abnormalities, e.g., GRIK4 and NPAS3, and mental retardation, on the other hand, with the symptom-profiles of schizopsychosis provide further evidence of emerging biomarkers of biological inheritance factors. The involvement of dopamine D1 and D2 receptors, particularly in prefrontal region, with regard to functional integrity of cognitive systems is reviewed. It would appear that considerations of these disorders imply that one essential hub around which much of the neuropathology revolves may be observed in the various expressions of the cognitive and structural insufficiency. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Apr 32: 876-80 |
| PMID | 18289755 |
| Title | No genetic association between polymorphisms in the kainate-type glutamate receptor gene, GRIK4, and schizophrenia in the Chinese population. |
| Abstract | schizophrenia is a chronic psychiatric disorder with a strong genetic component. Several studies have suggested that dysfunctions in the glutamatergic transmission are linked to the pathogenesis of schizophrenia, and that the kainate ionotropic glutamate receptors are involved in this mechanism. A recent study provides cytogenetic and genetic evidence to support a role for the kainate-type glutamate receptor gene (GRIK4), in schizophrenia. A systematic case-control association study of GRIK4 involving a Scottish population found that three SNPs, rs4935752, rs6589846 and rs4430518, were associated with schizophrenia. Here, we investigated rs4935752, rs6589846, rs4430518 and other 2 SNPs within the GRIK4 gene in an association study of the Chinese population. Our sample consisted of 288 schizophrenia and 288 control subjects. All recruits were Han Chinese drawn from the city of Shanghai. No individual SNP nor any haplotype was associated with schizophrenia in our study. These results suggest that the five SNPs within the GRIK4 gene are unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Neurotox Res 2008 Oct 14: 113-20 |
| PMID | 19073419 |
| Title | Chromosome abnormalities, mental retardation and the search for genes in bipolar disorder and schizophrenia. |
| Abstract | Genetic factors contribute to schizophrenia and bipolar disorder, and linkage and association studies have been successful in identifying several candidate genes. However these genes explain only a very small part of the total population risk and the psychoses appear to be very heterogeneous with several models of genetic inheritance relevant to different groups of patients, including some cases caused by multiple common genetic variants, while others are single gene disorders. Studying chromosomal abnormalities is a useful strategy for identifying genes in illness, and patients with both mental retardation and psychosis form a special group where large chromosomal abnormalities detected by routine cytogenetic analysis are more prevalent than in patients with schizophrenia or bipolar disorder alone, or in the general population. Studying these patients provides valuable opportunities to identify genes contributing to psychoses. This review of the literature on large chromosomal rearrangements in patients with mental retardation and psychotic illness illustrates how schizophrenia and bipolar phenotypes are associated with a large number of different chromosomal disruptions. Recent genome wide association studies have identified an excess of small chromosomal deletions and duplications in schizophrenia, adding further support to the importance of chromosomal structural variation in psychotic illness. The genes GRIK4 and NPAS3, each associated with psychosis in patients with mental retardation are discussed to illustrate the value of rare cytogenetic events as a means to signpost neurobiological pathways of general importance for illness in the wider population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Proc. Natl. Acad. Sci. U.S.A. 2008 Sep 105: 14940-5 |
| PMID | 18824690 |
| Title | A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder. |
| Abstract | Underactivity of the glutamatergic system is an attractive model for the pathophysiology of several major mental illnesses. We previously described a chromosome abnormality disrupting the kainate class ionotropic glutamate receptor gene, GRIK4/KA1, in an individual with schizophrenia and learning disability (mental retardation). We also demonstrated in a case-control study that two physically separated haplotypes within this gene were significantly associated with increased risk of schizophrenia and decreased risk of bipolar disorder, respectively. The latter protective haplotype was located at the 3' end of the gene. We now report the identification from carriers of the protective haplotype of a deletion variant within the 3' untranslated region of the gene. The deletion allele also was found to be negatively associated with bipolar disorder in both initial (P = 0.00000019) and replication (P = 0.0107) case-control studies. Expression studies indicated that deletion-carrying mRNA transcripts were relatively more abundant. We postulate that this may be a direct consequence of the differences in the RNA secondary structures predicted for the insertion and deletion alleles. These data suggest a mechanism whereby the genetic protective effect is mediated through increased kainate receptor expression. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Neuroscience 2009 Nov 164: 331-43 |
| PMID | 19358880 |
| Title | The genetics of bipolar disorder. |
| Abstract | Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) have raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Psychiatr. Genet. 2009 Feb 19: 6-13 |
| PMID | 19125103 |
| Title | Association analysis of the glutamic acid decarboxylase 2 and the glutamine synthetase genes (GAD2, GLUL) with schizophrenia. |
| Abstract | As dysfunction of glutamatergic neurotransmission is one of the plausible hypotheses for the pathogenesis of schizophrenia, genes involved in the glutamate neurotransmitter system are candidates for schizophrenia susceptibility. The aim of this study is to clarify the contribution of two genes encoding glutamate metabolic enzymes: the glutamic acid decarboxylase 2 gene (GAD2) and the glutamine synthetase gene (GLUL), in schizophrenia. We genotyped 300 Japanese schizophrenia patients and 300 healthy controls for 14 single nucleotide polymorphisms (SNPs) in GAD2 (approximately 91 kb in size) and six SNPs in GLUL (approximately 14 kb in size). We examined 'single-point' association as well as pairwise haplotype association for all SNPs with schizophrenia. We observed no significant 'single-point' associations with the disease in any of the 20 SNPs after correction for multiple testing using False Discovery Rate. We also observed no significant haplotype associations with False Discovery Rate. Furthermore, we analyzed gene-gene interactions, including six glutamate receptor genes we have reported previously in the association studies of GRIA4, GRIN2D, GRIK3, GRIK4, GRIK5, and GRM3, using the multifactor dimensionality reduction method. The best interaction model, however, did not show the statistical significance. These results suggest that GAD2 and GLUL do not play a major role in schizophrenia pathogenesis and there is no gene-gene interaction between the eight genes in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Pharmacogenet. Genomics 2011 Apr 21: 206-16 |
| PMID | 20859245 |
| Title | Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol. |
| Abstract | The glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments. We investigated a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol. We studied a sample of 101 acutely ill psychotic patients. We then validated our result in two independent samples from Slovenia (n=71 and n=118) of schizophrenic patients treated with antipsychotics. We both investigated the antipsychotic effect (Positive and Negative Syndrome Scale) and motor side effect (Extrapyramidal Symptom Rating Scale) at baseline and days 3, 7, 14, 21 and 28. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures of analysis of variance, P=0.0002), followed by a subsequent adaptation, probably dependent on haloperidol doses down titration. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher Extrapyramidal symptom rating scale scores (overall P=0.01, haplotype P=0.000001). We successfully replicated this finding in the two independent samples from Slovenia. This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Behav. Brain Res. 2012 Mar 228: 406-14 |
| PMID | 22203159 |
| Title | Genetic ablation of the GluK4 kainate receptor subunit causes anxiolytic and antidepressant-like behavior in mice. |
| Abstract | There is a clear link between dysregulation of glutamatergic signaling and mood disorders. Genetic variants in the glutamate receptor gene GRIK4, which encodes the kainate receptor subunit GluK4, alter the susceptibility for depression, bipolar disorder and schizophrenia. Here we demonstrate that GRIK4(-/-) mice have reduced anxiety and an antidepressant-like phenotype. In the elevated zero-maze, a test for anxiety and risk taking behavior, GRIK4(-/-) mice spent significantly more time exploring the open areas of the maze. In anxiogenic tests of marble-burying and novelty-induced suppression of feeding, anxiety-like behavior was consistently reduced in knockout animals. In the forced swim test, a test of learned helplessness that is used to determine depression-like behavior, knockout mice demonstrated significantly less immobility suggesting that GRIK4 ablation has an antidepressant-like effect. Finally, in the sucrose preference test, a test for anhedonia in rodents, GRIK4(-/-) mice demonstrated increased sucrose preference. Expression of the GluK4 receptor subunit in the forebrain is restricted to the CA3 region of the hippocampus and dentate gyrus regions where KARs are known to modulate synaptic plasticity. We tested whether GRIK4 ablation had effects on mossy fiber (MF) plasticity and found there to be a significant impairment in LTP likely through a loss of KAR modulation of excitability of the presynaptic MF axons. These studies demonstrate a clear anxiolytic and antidepressant phenotype associated with ablation of GRIK4 and a parallel disruption in hippocampal plasticity, providing support for the importance of this receptor subunit in mood disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Am. J. Med. Genet. A 2014 Feb 164A: 456-60 |
| PMID | 24449200 |
| Title | 1p34.3 deletion involving GRIK3: Further clinical implication of GRIK family glutamate receptors in the pathogenesis of developmental delay. |
| Abstract | A growing body of evidence suggests an association between microdeletion/microduplication and schizophrenia/intellectual disability. Abnormal neurogenesis and neurotransmission have been implicated in the pathogenesis of these neuropsychiatric and neurodevelopmental disorders. The kainate/AMPA-type ionotropic glutamate receptor (GRIK?=?glutamate receptor, ionotropic, kainate) plays a critical role in synaptic potentiation, which is an essential process for learning and memory. Among the five known GRIK family members, haploinsufficiency of GRIK1, GRIK2, and GRIK4 are known to cause developmental delay, whereas the roles of GRIK3 and GRIK5 remain unknown. Herein, we report on a girl who presented with a severe developmental delay predominantly affecting her language and fine motor skills. She had a 2.6-Mb microdeletion in 1p34.3 involving GRIK3, which encodes a principal subunit of the kainate-type ionotropic glutamate receptor. Given its strong expression pattern in the central nervous system and the biological function of GRIK3 in presynaptic neurotransmission, the haploinsufficiency of GRIK3 is likely to be responsible for the severe developmental delay in the proposita. A review of genetic alterations and the phenotypic effects of all the GRIK family members support this hypothesis. The current observation of a microdeletion involving GRIK3, a kainate-type ionotropic glutamate receptor subunit, and the neurodevelopmental manifestation in the absence of major dysmorphism provides further clinical implication of the possible role of GRIK family glutamate receptors in the pathogenesis of developmental delay. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Schizophr. Res. 2016 Jan 170: 30-40 |
| PMID | 26597662 |
| Title | Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study. |
| Abstract | The Consortium on the Genetics of schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic |