Association study of polymorphisms in the GluR7, KA1 and KA2 kainate receptor genes (GRIK3, GRIK4, GRIK5) with schizophrenia

Shibata, Hiroki; Aramaki, Toshihiro; Sakai, Mayumi; Ninomiya, Hideaki; Tashiro, Nobutada; Iwata, Nakao; Ozaki, Norio; Fukumaki, Yasuyuki

doi:10.1016/j.psychres.2005.07.015

Cited by 40 publications

(22 citation statements)

References 22 publications

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“…Recently, an association study was carried out on GRIK4 in Japanese schizophrenia patients. 41 The study failed to identify any statistically significant single SNP or haplotype associations despite good marker coverage. Explanations for this might be the modest size of the study (100 cases, 100 controls) and the different population studied.…”

Section: Discussionmentioning

confidence: 92%

Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder

et al. 2006

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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.

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Section: Discussionmentioning

confidence: 92%

Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder

et al. 2006

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“…GluR7 (GRIK3) has been proposed to be linked to schizophrenia in two genetic studies, one associating the disease with a GluR7 polymorphism (ser310ala; Begni et al 2002) and the other reporting aberration in GluR7 DNA copy-number, among a number of other important proteins (Wilson et al 2006). However, none of the kainate-receptor genes have been reported to be linked to schizophrenia in the Japanese population (Shibata et al 2001(Shibata et al , 2002(Shibata et al , 2006, indicating that the link between GluR7 and schizophrenia needs to be further explored. In schizophrenic patients, maternal transmission disequilibrium of GRIK2 (GluR6) also suggests a role for this gene as a susceptibility gene for schizophrenia (Bah et al 2004).…”

Section: Human Molecular Genetic Studiesmentioning

confidence: 99%

Kainate receptors

2006

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Kainate receptors form a family of ionotropic glutamate receptors that appear to play a special role in the regulation of the activity of synaptic networks. This review first describes briefly the molecular and pharmacological properties of native and recombinant kainate receptors. It then attempts to outline the general principles that appear to govern the function of kainate receptors in the activity of synaptic networks under physiological conditions. It subsequently describes the way that kainate receptors are involved in synaptic integration, synaptic plasticity, the regulation of neurotransmitter release and the control of neuronal excitability, and the manner in which they might play an important role in synaptogenesis and synaptic maturation. These functions require the proper subcellular localization of kainate receptors in specific functional domains of the neuron, necessitating complex cellular and molecular trafficking events. We show that our comprehension of these mechanisms is just starting to emerge. Finally, this review presents evidence that implicates kainate receptors in pathophysiological conditions such as epilepsy, excitotoxicity and pain, and that shows that these receptors represent promising therapeutic targets.

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“…We carried out a case control association study for evidence that GRIK4 is a risk factor for schizophrenia in patients in the general population without chromosomal abnormalities or mental retardation, using twenty seven tagging SNPs spanning the gene, as predicted from the International HapMap project data HapMap (Pickard et al, 2005). This may not be the case in other populations as a recent study in 100 cases and 100 controls failed to detect association between GRIK4 and schizophrenia in Japanese patients (Shibata et al, 2006) Neuregulin (NRG1) Neuregulin (NRG1) on chromosome 8p12 is a large and complex gene spanning more than one Mb. At another region on the gene two SNPs each had significantly different frequencies in bipolar disorder compared to controls.…”

Section: Glutamate Receptor Ionotropic Kainate Type 4 (Grik4)mentioning

confidence: 99%

Are some genetic risk factors common to schizophrenia, bipolar disorder and depression? evidence fromDISC1, GRIK4 andNRG1

et al. 2007

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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.

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Association study of polymorphisms in the GluR7, KA1 and KA2 kainate receptor genes (GRIK3, GRIK4, GRIK5) with schizophrenia

Cited by 40 publications

References 22 publications

Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder

Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder

Kainate receptors

Are some genetic risk factors common to schizophrenia, bipolar disorder and depression? evidence fromDISC1, GRIK4 andNRG1

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