Schizophrenia and GABAA receptor subunit genes

Byerley, William; Bailey, Mark E.S.; Hicks, Andrew A.; Riley, B.P.; Darlison, Mark G.; Holik, John; Hoff, M.; Umar, Farah; Reimherr, Frederick W.; Wender, Paul H.; Myles-Worsley, Marina; Waldo, Merilyne; Freedman, Robert; Johnson, Keith; Coon, Hilary

doi:10.1097/00041444-199521000-00004

Cited by 13 publications

(6 citation statements)

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“…Only CHRNA7 and its partial duplication are currently known to lie in the interval D15S1043-D15S1010 . There is no evidence of any linkage of schizophrenia to the GABA A receptor subunit cluster (Byerley et al, 1995) or to MAP1A (this study). Given the current data and the significant results for haplotype transmission, CHRNA7 or its partial duplication must be regarded as the most promising candidate for a schizophrenia susceptibility gene in this chromosome region.…”

Section: Discussioncontrasting

confidence: 56%

Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families

Riley¹,

Makoff²,

Mogudi-Carter

et al. 2000

Am. J. Med. Genet.

114

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Recent reports have strongly linked markers near the alpha-7 nicotinic cholinergic receptor subunit gene on human chromosome 15q13-q14 to a sensory gating deficit common in schizophrenics, and have shown positive though non-significant results linking this region to the primary phenotype of schizophrenia in a sample of North American families. We therefore tested for linkage between markers in this region of chromosome 15q and schizophrenia in a sample of 15 multiply affected and 5 single case families with schizophrenia drawn from the Bantu-speaking black population of South Africa. An initial replication using markers from the original study gave an affected-only LOD score maximum of 1.08 under a recessive model at Theta=0.00 for D15S1360, a dinucleotide polymorphism found on the same YAC as the alpha-7 receptor gene. Nonparametric affected-only multipoint analysis gave a Z-score of 1. 29, P=0.098, for D15S1360, and Z=1.45, p=0.075 for D15S118. We then increased the resolution of the map with an extended set of 20 markers. Again, two peaks were observed, with NPL scores of 1.81, p=0.037, at D15S1043 and 1.79 at D15S1360 and 1.80 at D15S1010, both p=0.037. Transmission disequilibrium testing of data from D15S1360 gave an allele-wise and genotype-wise chi(2) of 6.59, 2 df, p=0.037. Haplotype transmission disequilibrium testing using a restricted allele and haplotype set from D15S1043 and D15S1360 gave a global chi(2) of 10.647, 4 df, P=0.007, and a maximum chi(2) of 6.567, 1 df, P=0.004 for excess transmission of the 1.2 haplotype into affected offspring. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:196-201, 2000.

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Section: Discussioncontrasting

confidence: 56%

Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families

Riley¹,

Makoff²,

Mogudi-Carter

et al. 2000

Am. J. Med. Genet.

114

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“…Observations of abnormalities in markers of glutamatergic neurotransmission in the hippocampus and the entorhinal, cingulate, orbital, and prefrontal cortices of patients with schizophrenia (3,13,(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43), the critical role of glutamatergic systems in learning and memory (44,45), and the clear evidence for the neurotoxicity of glutamate (28,46,47) have given further credence to the potential involvement of the glutamatergic system in schizophrenia.…”

Section: Objectivementioning

confidence: 99%

N-Methyl-d-Aspartic Acid Receptor Expression in the Dorsolateral Prefrontal Cortex of Elderly Patients With Schizophrenia

Dracheva

Marras²,

Elhakem³

et al. 2001

AJP

181

103

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Objective:The N-methyl-D-aspartic acid (NMDA) class of glutamate receptors has received attention in the pathophysiology of schizophrenia because of the similarity between some schizophrenic symptoms and symptoms caused by NMDA antagonists. To determine if NMDA receptor abnormalities were present at the mRNA level, expression of NMDA receptor (NR) subunits NR 1 , NR 2A , and NR 2B was measured in specimens from the dorsolateral prefrontal cortex and the occipital cortex of elderly patients with schizophrenia and normal elderly subjects.Method: Postmortem specimens from antemortem assessed and diagnosed elderly patients with schizophrenia (N=26) were compared with those from a neuropathologically and neuropsychiatrically normal elderly comparison group (N=13) and from patients with Alzheimer's disease (N=10). The mRNA expression of the NR 1 , NR 2A , and NR 2B subunits and of postsynaptic density 95 (PSD-95), a protein associated with postsynaptic NMDA receptors, was studied with quantitative real-time reverse transcriptase polymerase chain reaction.Results: Expression of NR 1 and NR 2A but not NR 2B subunits was higher in the dorsolateral prefrontal cortex and the occipital cortex of patients with schizophrenia than in the normal and Alzheimer's disease groups. In contrast, NR 1 expression was significantly lower in the Alzheimer's disease group. Occipital cortex expression of PSD-95 was higher in the schizophrenic subjects and correlated strongly with the expression of NR 2A and NR 2B in both cortical regions and with expression of NR 1 in the occipital cortex. These results were not influenced by neuroleptic exposure history, postmortem interval, or age of the subject.Conclusions: NMDA receptor subunits are abnormally expressed in elderly patients with schizophrenia. The disproportionate expression of the NR 1 and NR 2A subunits relative to NR 2B expression may have implications for the pathophysiology of schizophrenia and the sensitivity of schizophrenic patients to glutamate and glutamatergic drugs. Several neurochemical hypotheses have been proposed to explain the origin of schizophrenia, including abnormal dopamine, serotonin (5-HT), γ-aminobutyric acid (GABA), and/or glutamate neurotransmission in different regions of the brain (1-8). Abnormalities in the dorsolateral prefrontal cortex have figured prominently in many of these hypotheses, in part due to results of in vivo imaging and neuroanatomical studies (9-11), although there is evidence for structural, metabolic, and neurochemical abnormalities in many other brain regions, including the thalamus, the hippocampus, and the cingulate and entorhinal cortices (1,(12)(13)(14)(15)(16)(17)(18)(19).Strong evidence supporting an association between glutamatergic hypofunction and schizophrenia has come from pharmacological studies showing that N-methyl-Daspartic acid (NMDA) receptor antagonists such as phencyclidine and ketamine can induce many of the psychotic signs and symptoms of schizophrenia in normal subjects, as well as exacerbate these signs and symptom...

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“…The human ␣1-subunit gene contains a highly polymorphic (dC-dA) n repeat, varying from 1-14 dinucleotides [Walsh et al, 1992]. However, previous studies in schizophrenia [Byerley et al, 1995] and mood disorders [De Bruyn et al, 1996;Coon et al, 1994] failed to reveal any GABRA1 involvement. We then hypothesized that GABRA1 variants could be associated with the symptomatology of major psychoses and could influence the association of DRD4 with delusional symptoms.…”

Section: Introductionmentioning

confidence: 99%

No interaction of GABAA alpha-1 subunit and dopamine receptor D4 exon 3 genes in symptomatology of major psychoses

et al. 1999

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Previously, we reported on an association of the dopamine receptor D4 (DRD4) gene with delusional symptomatology of major psychoses. However, despite the strength of the association, it only accounted for 2% of the variance, indicating that contributions from other genes were probable. In the present study, we investigated the original cohort of subjects to evaluate the gene for the gamma-aminobutyric acid type A (GABA(A)) receptor alpha-1 subunit (GABRA1). The possible association of GABRA1 with the psychopathology of major psychoses was tested both alone and in interaction with DRD4. Four hundred and sixty-one inpatients affected by major psychoses were assessed by the operational criteria checklist for psychotic illness (OPCRIT) and were also typed for the DRD4 and GABRA1 variants using PCR techniques. Mania, depression, delusion, and disorganization were the four symptomatologic factors used as phenotype definitions. GABRA1 variants were not associated with these symptomatologic factors, and consideration of possible stratification effects such as sex and psychiatric diagnosis also did not reveal any association. GABRA1 variants did not significantly influence the association of DRD4 with delusional symptoms. No interaction was observed on the other symptom factors. The GABA(A) alpha-1 subunit gene does not, therefore, interact with DRD4 in the symptomatology of major psychoses.

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Schizophrenia and GABAA receptor subunit genes

Cited by 13 publications

References 0 publications

Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families

Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families

N-Methyl-d-Aspartic Acid Receptor Expression in the Dorsolateral Prefrontal Cortex of Elderly Patients With Schizophrenia

No interaction of GABAA alpha-1 subunit and dopamine receptor D4 exon 3 genes in symptomatology of major psychoses

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