Maternal transmission disequilibrium of the glutamate receptor GRIK2 in schizophrenia
ABSTRACT Schizophrenia is characterized by thought disorders, hallucinations and delusions. Genetic studies have shown a high linkage at chromosome 6q16-21. Among the genes located in this region is the glutamate receptor ionotropic kainate 2 gene (GRIK2 or GLUR6), a functional candidate for susceptibility to schizophrenia. In this study, transmission of GRIK2 was evaluated in 356 schizophrenic patients from three different clinical centers. Whereas paternal transmission shows equilibrium, we observed maternal transmission disequilibrium of GRIK2 in the largest population (p=0.03), which was still significant when all populations were added (p=0.05). These results are similar to the maternal GRIK2 transmission disequilibrium previously reported for autism, and support the presence of a susceptibility gene for schizophrenia at 6q16.
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ABSTRACT: Anorexia nervosa (AN) is a severe and complex psychiatric disorder with a significant genetic contribution. Previously, we found an association between AN and the 158Val/Met polymorphism of the catechol-O-methyltransferase (COMT) gene in a family-based study of 51 Israeli AN trios. In the present study, we extended the original sample to include 85 family trios [66 AN restricting (AN-R) and 19 bingeing/purging (AN-BP) subtype] and performed a family-based transmission disequilibrium test (TDT) analysis for five SNPs in the COMT and two in the adjacent ARVCF gene. Association was found between AN-R and several SNPs in the COMT-ARVCF region including the 158Val/Met polymorphism. TDT analysis of 5-SNP haplotypes in AN-R trios revealed an overall statistically significant transmission disequilibrium (P < 0.001). Specifically, haplotype B [COMT-186C-408G-472G(158Val)-ARVCF-659C(220Pro)-524T(175Val)] was preferentially transmitted (P < 0.001) from parents of AN-R patients to their affected daughters, while haplotype A [COMT-186T-408C-472A(158Met)-ARVCF-659T(220Leu)-524C(175Ala)] was preferentially (P = 0.01) not transmitted. Haplotype B was associated with increased risk (RR 3.38; 0.95CI 1.98-6.43) while haplotype A exhibited a protective effect (RR 0.40; 0.95CI 0.21-0.70) for AN-R. Preferential transmission of the risk alleles and haplotypes from the parents was mostly contributed by the fathers. No significant transmission disequilibrium of alleles or haplotypes was found for AN-BP trios. The risk and protective haplotypes may carry molecular variations in the COMT gene or its vicinity that are relevant to the pathophysiology of restrictive anorexia nervosa in the Israeli-Jewish population.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 11/2005; 139B(1):45-50. DOI:10.1002/ajmg.b.30230 · 3.27 Impact Factor
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ABSTRACT: Schizophrenia is a severe mental illness affecting millions of people worldwide, with a substantial impact on patients, family, and society. Recent studies have established support for a hypothesis of abnormal glutamatergic neurotransmission in specific brain regions in schizophrenia involving myriad molecules associated with glutamate signaling. After a brief description of these molecules of the glutamatergic synapse, this review focuses on recent experimental evidence for glutamate abnormalities in schizophrenia, and discusses data from genetic, postmortem brain, in vivo imaging, and pharmacologic studies. These convergent findings implicate altered glutamate neurotransmission in the pathophysiology of schizophrenia, and suggest that novel therapeutic strategies targeted at modulation of glutamate neurotransmission may be useful in this illness.Current Psychosis and Therapeutics Reports 01/2006; 4(1):27-34. DOI:10.1007/BF02629411
Article: Kainate receptor physiology[Show abstract] [Hide abstract]
ABSTRACT: Glutamate receptors constitute a complex signalling system at most of the excitatory synapses in the brain. Of the known ionotropic glutamate receptors, kainate receptors are ubiquitous in the central nervous system, and a considerable amount of data indicates that this class of receptors is present at both sides of the synapse. Pre- and postsynaptic kainate receptors are able to regulate both transmission of information and excitability in a synapse-specific manner. Proteins interacting with kainate receptor subunits are being identified and functional studies have provided evidence of the existence of a dual signalling system. It has become clear that these receptors have a role in synaptic plasticity and that they might also have a fundamental role in epilepsy through the strategic control of network excitability. However, the role of kainate receptors in other brain pathologies remains obscure.Current Opinion in Pharmacology 03/2006; 6(1):89-97. DOI:10.1016/j.coph.2005.08.004 · 4.23 Impact Factor