Association study between the NMDA receptor 2B subunit gene (GRIN2B) and schizophrenia: A HuGE review and meta-analysis

Li, Dawei; He, Lin

doi:10.1097/01.gim.0000250507.96760.4b

Cited by 70 publications

(41 citation statements)

References 25 publications

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“…More recently, a study by Martucci et al 23 also detected an association between GRIN2B DNA variants and both BP and schizophrenia, and a metaanalysis supported the association with schizophrenia. 24 Our current results provide additional support for the involvement of GRIN2B in BP and indicate that this gene merits further study.…”

Section: Discussionsupporting

confidence: 66%

“…Furthermore, markers in GRIN2B have been associated with schizophrenia by many studies and supported by a recent meta-analysis. 24 This convergence of evidence led us to examine the hypothesis that GRIN2B might be responsible for the observed linkage signal. We first examined whether the recessive genetic model supported by the linkage analysis also improved evidence of association.…”

Section: Resultsmentioning

confidence: 99%

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Stage II follow-up on a linkage scan for bipolar disorder in the Ashkenazim provides suggestive evidence for chromosome 12p and the GRIN2B gene

Avramopoulos

Lasseter

Fallin

et al. 2007

Genetics in Medicine

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Purpose: We had previously performed a genome-wide linkage scan for bipolar affective disorder in an Ashkenazi Jewish sample, a population likely to have reduced genetic heterogeneity. This study is a second stage follow-up focusing on regions that showed positive linkage scores in our previous scan but were not fine-mapped at that time. Methods:We genotyped an additional 145 highly polymorphic microsatellites and conducted linkage analyses using standard laboratory and analytical methods. Results: We saw an improvement of the evidence for linkage in most regions, with the most notable change on chromosome 12p13.1-p12.3, where the evidence of linkage is now suggestive. This region harbors the gene encoding the ionotropic glutamate receptor subunit 2B (GRIN2B), a gene that previously yielded evidence for association in a candidate gene study on 323 Ashkenazi Jewish bipolar case-parent trios. We find that the evidence for linkage is significantly correlated with the presence of the putative high-risk allele identified in our candidate gene study. Bipolar disorder (BP) is a common, disabling psychiatric disease with a lifetime prevalence reaching 2% (American Psychiatric Association, 1994). Several types of BP are recognized in the Diagnostic and Statistical Manual, fourth edition that vary in the nature and duration of symptoms and the extent of disability. One well-established diagnostic classification focuses on the intensity of manic symptoms recognizing two categories, BPI and BPII, with BPII showing episodes of less severe mania described as hypomania. Evidence from family, twin, and adoption studies strongly supports a genetic component of BP, with heritability estimates of 60 -80% 1 and risk to first-degree relatives of 5-10%. 2 Although segregation analyses have been inconclusive, they suggest a complex and multigenic susceptibility to BP, involving both genes and environment. Many genome-wide linkage scans and three meta-analyses have been reported, 3-13 identifying multiple candidate genomic regions but with inconsistent replication across studies. One potential reason for this lack of consistency in linkage scan results could be the inconsistency in the definition of the affection status across studies, regarding both the diagnosis and the inclusion of BPI, BPII, and schizoaffective disorder, a condition in which patients present both psychotic and affective symptoms, and which some investigators consider a variant of schizophrenia and others a variant of BP. Another likely reason for the inconsistency in linkage results is the high likelihood of locus heterogeneity, especially if individual genes with small or moderate effects on risk are present or possibly genes that interact are involved. One strategy to reduce locus heterogeneity is to study families from a relatively genetically isolated population that originated from a small number of founders. 14, 15 We recently employed this approach in a genome-wide linkage scan of 41 Ashkenazi Jewish (AJ) families with BP. 16 More recently we followed the sa...

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Section: Discussionsupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Stage II follow-up on a linkage scan for bipolar disorder in the Ashkenazim provides suggestive evidence for chromosome 12p and the GRIN2B gene

Avramopoulos

Lasseter

Fallin

et al. 2007

Genetics in Medicine

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“…As a result a highly significant association with schizophrenia was found for polymorphisms of the 5' end of GRIN1, but not for GRIN2A polymorphisms [73]. In a current meta-analysis GRIN2B resulted in a statistically significant association with schizophrenia, which supports the involvement of the glutamate system in the pathogenesis of schizophrenia [74]. The GRIA1 gene encodes for one (GluR1) of the four ionotropic AMPA receptor subunits and has been found to be decreased in the brain of some schizophrenic patients.…”

Section: The Glutamatergic Hypothesis Of Schizophreniamentioning

confidence: 43%

Molecular Mechanisms of Schizophrenia

Lang¹,

Puls²,

Müller³

et al. 2007

Cell Physiol Biochem

252

165

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Schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.

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“…4 Despite such disappointments, genetic research has captured public attention. Relevant findings have been featured by the media with notable zeal, proclaiming breakthrough evidence that links specific genes, markers, or chromosomal abnormalities with a variety of human diseases and disorders (e.g., schizophrenia), 5 tendencies (e.g., criminality), 6 and behaviors (e.g., novelty seeking). 7 Unfortunately, these findings were often followed by replication failures.…”

Section: Introductionmentioning

confidence: 99%

The effects of learning about one’s own genetic susceptibility to alcoholism: a randomized experiment

Dar‐Nimrod

Zuckerman

Duberstein

2013

Genetics in Medicine

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Association study between the NMDA receptor 2B subunit gene (GRIN2B) and schizophrenia: A HuGE review and meta-analysis

Cited by 70 publications

References 25 publications

Stage II follow-up on a linkage scan for bipolar disorder in the Ashkenazim provides suggestive evidence for chromosome 12p and the GRIN2B gene

Stage II follow-up on a linkage scan for bipolar disorder in the Ashkenazim provides suggestive evidence for chromosome 12p and the GRIN2B gene

Molecular Mechanisms of Schizophrenia

The effects of learning about one’s own genetic susceptibility to alcoholism: a randomized experiment

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