| 1 | Am. J. Hum. Genet. 2005 Dec 77: 918-36 |
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| PMID | 16380905 |
| Title | Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. |
| Abstract | Bipolar, schizophrenia, and schizoaffective disorders are common, highly heritable psychiatric disorders, for which familial coaggregation, as well as epidemiological and genetic evidence, suggests overlapping etiologies. No definitive susceptibility genes have yet been identified for any of these disorders. Genetic heterogeneity, combined with phenotypic imprecision and poor marker coverage, has contributed to the difficulty in defining risk variants. We focused on families of Ashkenazi Jewish descent, to reduce genetic heterogeneity, and, as a precursor to genomewide association studies, we undertook a single-nucleotide polymorphism (SNP) genotyping screen of 64 candidate genes (440 SNPs) chosen on the basis of previous linkage or of association and/or biological relevance. We genotyped an average of 6.9 SNPs per gene, with an average density of 1 SNP per 11.9 kb in 323 bipolar I disorder and 274 schizophrenia or schizoaffective Ashkenazi case-parent trios. Using single-SNP and haplotype-based transmission/disequilibrium tests, we ranked genes on the basis of strength of association (P<.01). Six genes (DAO, GRM3, GRM4, GRIN2B, IL2RB, and TUBA8) met this criterion for bipolar I disorder; only DAO has been previously associated with bipolar disorder. Six genes (RGS4, SCA1, GRM4, DPYSL2, NOS1, and GRID1) met this criterion for schizophrenia or schizoaffective disorder; five replicate previous associations, and one, GRID1, shows a novel association with schizophrenia. In addition, six genes (DPYSL2, DTNBP1, G30/G72, GRID1, GRM4, and NOS1) showed overlapping suggestive evidence of association in both disorders. These results may help to prioritize candidate genes for future study from among the many suspected/proposed for schizophrenia and bipolar disorders. They provide further support for shared genetic susceptibility between these two disorders that involve glutamate-signaling pathways. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 2 | Schizophr. Res. 2007 Jul 93: 385-90 |
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| PMID | 17490860 |
| Title | A case-control association study between the GRID1 gene and schizophrenia in the Chinese Northern Han population. |
| Abstract | The glutamatergic dysfunction hypothesis of schizophrenia implicates the genes involved in glutamatergic transmission as strong candidates for schizophrenia-susceptibility. Recent linkage and association studies have identified the glutamate receptor, ionotropic, delta 1 gene GRID1 on 10q22 as a strong candidate for schizophrenia. In this current association study, we genotyped five genetic variants within the GRID1 gene in 567 Chinese Han subjects recruited from Northeast of China (260 schizophrenics and 307 normal controls). Four SNPs, rs1902666 (P=0.024), rs2814351 (P=0.027), rs11591408 (P=0.0000107) and rs999383 (P=0.000093) were found to be significantly associated with schizophrenia. Haplotype analysis also revealed significance with global P values of 0.0081 and 0.00076 for SNPs 1-2 and SNPs 3-4-5 haplotypes, respectively. Our results strongly support previously reported association studies, implicating GRID1 in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 3 | Schizophr. Res. 2007 Jul 93: 385-90 |
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| PMID | 17490860 |
| Title | A case-control association study between the GRID1 gene and schizophrenia in the Chinese Northern Han population. |
| Abstract | The glutamatergic dysfunction hypothesis of schizophrenia implicates the genes involved in glutamatergic transmission as strong candidates for schizophrenia-susceptibility. Recent linkage and association studies have identified the glutamate receptor, ionotropic, delta 1 gene GRID1 on 10q22 as a strong candidate for schizophrenia. In this current association study, we genotyped five genetic variants within the GRID1 gene in 567 Chinese Han subjects recruited from Northeast of China (260 schizophrenics and 307 normal controls). Four SNPs, rs1902666 (P=0.024), rs2814351 (P=0.027), rs11591408 (P=0.0000107) and rs999383 (P=0.000093) were found to be significantly associated with schizophrenia. Haplotype analysis also revealed significance with global P values of 0.0081 and 0.00076 for SNPs 1-2 and SNPs 3-4-5 haplotypes, respectively. Our results strongly support previously reported association studies, implicating GRID1 in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 4 | Schizophr. Res. 2009 Apr 109: 86-9 |
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| PMID | 19264453 |
| Title | A MicroRNA gene is hosted in an intron of a schizophrenia-susceptibility gene. |
| Abstract | schizophrenia (SZ) is a neuropsychiatric disorder that affects about 1% of the adult population. Numerous genes have been implicated in SZ susceptibility. MicroRNAs (miRNA) are small RNA molecules that regulate the translation of mRNAs via interactions with their 3' untranslated regions. Identification of known miRNA targets on all human genes indicated that miRNA-346 targets SZ susceptibility genes listed in the schizophreniaGene database twice as frequently as expected relative to other genes in the genome. The gene encoding this miRNA, miR-346, is located in intron 2 of the glutamate receptor ionotropic delta 1 (GRID1) gene, which has been previously implicated in SZ susceptibility. We used quantitative real-time PCR to determine the expression levels of miR-346 and GRID1 using brain RNA samples from the Stanley Array Collection, Stanley Medical Research Institute. Expression of both miR-346 and GRID1 is lower in SZ patients than that in normal controls (P=0.017 and 0.086, respectively). However, the expression of miR-346 and GRID1 is less correlated in SZ patients than in bipolar patients or in normal controls. This study implicates the importance of a miRNA in SZ. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 5 | Schizophr. Res. 2009 Jun 111: 123-30 |
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| PMID | 19346103 |
| Title | Dissection of phenotype reveals possible association between schizophrenia and Glutamate Receptor Delta 1 (GRID1) gene promoter. |
| Abstract | Recent linkage and association data have implicated the Glutamate Receptor Delta 1 (GRID1) locus in the etiology of schizophrenia. In this study, we sought to test whether variants in the promoter region are associated with this disorder. The distribution of CpG islands, which are known to be relevant for transcriptional regulation, was computationally determined at the GRID1 locus, and the putative transcriptional regulatory region at the 5'-terminus was systematically tagged using HapMap data. Genotype analyses were performed with 22 haplotype-tagging single nucleotide polymorphisms (htSNPs) in a German sample of 919 schizophrenia patients and 773 controls. The study also included two SNPs in intron 2 and one in intron 3 which have been found to be significantly associated with schizophrenia in previous studies. For the transcriptional regulatory region, association was obtained with rs3814614 (p=0.0193), rs10749535 (p=0.0245), and rs11201985 (p=0.0222). For all further analyses, the patient samples were divided into more homogeneous subgroups according to sex, age at onset, positive family history of schizophrenia and lifetime history of major depression. The p-value of the schizophrenia association finding for the three markers decreased by approximately one order of magnitude, despite the reduction in the total sample size. Marker rs3814614 (unadjusted p=0.0005), located approximately 2.0 kb from the transcriptional start point, also withstood a two-step correction for multiple testing (p=0.030). No support was obtained for previously reported associations with the intronic markers. Our results suggest that genetic variants in the GRID1 transcriptional regulatory region may play a role in the etiology of schizophrenia, and that future association studies of schizophrenia may require stratification to ensure more homogeneous patient subgroups. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 6 | PLoS ONE 2012 -1 7: e32969 |
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| PMID | 22412961 |
| Title | Deletion of glutamate delta-1 receptor in mouse leads to aberrant emotional and social behaviors. |
| Abstract | The delta family of ionotropic glutamate receptors consists of glutamate ?1 (GluD1) and glutamate ?2 (GluD2) receptors. While the role of GluD2 in the regulation of cerebellar physiology is well understood, the function of GluD1 in the central nervous system remains elusive. We demonstrate for the first time that deletion of GluD1 leads to abnormal emotional and social behaviors. We found that GluD1 knockout mice (GluD1 KO) were hyperactive, manifested lower anxiety-like behavior, depression-like behavior in a forced swim test and robust aggression in the resident-intruder test. Chronic lithium rescued the depression-like behavior in GluD1 KO. GluD1 KO mice also manifested deficits in social interaction. In the sociability test, GluD1 KO mice spent more time interacting with an inanimate object compared to a conspecific mouse. D-Cycloserine (DCS) administration was able to rescue social interaction deficits observed in GluD1 KO mice. At a molecular level synaptoneurosome preparations revealed lower GluA1 and GluA2 subunit expression in the prefrontal cortex and higher GluA1, GluK2 and PSD95 expression in the amygdala of GluD1 KO. Moreover, DCS normalized the lower GluA1 expression in prefrontal cortex of GluD1 KO. We propose that deletion of GluD1 leads to aberrant circuitry in prefrontal cortex and amygdala owing to its potential role in presynaptic differentiation and synapse formation. Furthermore, these findings are in agreement with the human genetic studies suggesting a strong association of GRID1 gene with several neuropsychiatric disorders including schizophrenia, bipolar disorder, autism spectrum disorders and major depressive disorder. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 7 | J Psychiatr Res 2012 Dec 46: 1531-9 |
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| PMID | 23017809 |
| Title | Glutamate receptor ? 1 (GRID1) genetic variation and brain structure in schizophrenia. |
| Abstract | Common genetic variation in the promoter region of the glutamate receptor delta 1 (GRID1) gene has recently been shown to confer increased risk for schizophrenia in several independent large samples. We analysed high-resolution magnetic resonance imaging (MRI) data from 62 patients with schizophrenia and 54 healthy controls using voxel-based morphometry (VBM) to assess the effect of single nucleotide polymorphism rs3814614 (located in the GRID1 promoter region), of which the T allele was identified as a risk factor in a previous association study. There were no effects of genotype or group × genotype interactions on total brain grey matter or white matter, but on regional grey matter. In healthy subjects, we identified a significant effect of rs3814614 genotype in the anterior thalamus (bilaterally), superior prefrontal cortex, and orbitofrontal cortex - in all cases with the homozygous risk genotype TT resulting in higher grey matter density. We did not find this association within the schizophrenia sample, where rs3814614 variation was only associated with grey matter reduction in TT homozygous subjects in medial parietal cortex and increased grey matter in right medial cerebellum. For white matter, we did not find significant genotype effects in healthy controls, and only minor effects within schizophrenia patients in the posterior temporal lobe white matter. Our data indicate that GRID1 rs3814614 genotype is related to grey matter variation in prefrontal and anterior thalamic brain areas in healthy subjects, but not in patients indicating a potential role of this schizophrenia candidate gene in thalamo-cortical functioning. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 8 | Transl Psychiatry 2015 -1 5: e541 |
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| PMID | 25849980 |
| Title | LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage. |
| Abstract | Genetic, environmental and neurodevelopmental factors are thought to underlie the onset of neuropsychiatric disorders such as schizophrenia. How these risk factors collectively contribute to pathology is unclear. Here, we present a mouse model of prenatal intracerebral hemorrhage--an identified risk factor for schizophrenia--using a serum-exposure paradigm. This model exhibits behavioral, neurochemical and schizophrenia-related gene expression alterations in adult females. Behavioral alterations in amphetamine-induced locomotion, prepulse inhibition, thigmotaxis and social interaction--in addition to increases in tyrosine hydroxylase-positive dopaminergic cells in the substantia nigra and ventral tegmental area and decreases in parvalbumin-positive cells in the prefrontal cortex--were induced upon prenatal serum exposure. Lysophosphatidic acid (LPA), a lipid component of serum, was identified as a key molecular initiator of schizophrenia-like sequelae induced by serum. Prenatal exposure to LPA alone phenocopied many of the schizophrenia-like alterations seen in the serum model, whereas pretreatment with an antagonist against the LPA receptor subtype LPA1 prevented many of the behavioral and neurochemical alterations. In addition, both prenatal serum and LPA exposure altered the expression of many genes and pathways related to schizophrenia, including the expression of Grin2b, Slc17a7 and GRID1. These findings demonstrate that aberrant LPA receptor signaling associated with fetal brain hemorrhage may contribute to the development of some neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 9 | Schizophr. Res. 2016 Jan 170: 30-40 |
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| 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, schizophrenics |