Association between GABA-A Receptor Alpha 5 Subunit Gene Locus and Schizophrenia of a Later Age of Onset

Abstract

Heritability is considered to be a major etiologic factor for schizophrenia. Among the genes considered as candidates for the disease, are those related to GABAergic neurotransmission. Our aim was to test for a genetic association between GABA-A receptor alpha 5 subunit gene locus (GABRA₅) and schizophrenia. Genotyping of the GABRA₅ locus was performed by the use of a dinucleotide (CA) repeat marker in 46 schizophrenic patients and 50 healthy individuals, all unrelated Greeks. Eight alleles were identified, 276–290 bp long. A nonsignificant excess of the 282-bp allele, which was found in a previous study in a Greek population to be associated with bipolar affective disorder, was observed in schizophrenic patients (33.8 vs. 23.9% in the controls). The frequency of this allele was 43.3% among patients with a later age of onset (over 25 years), differing at a statistically significant level from the controls (p < 0.05). These results suggest that common pathophysiological mechanisms may possibly underlie affective disorders and schizophrenia, at least in a subgroup of patients.

Mutational screening and association study of glutamate decarboxylase 1 as a candidate susceptibility gene for bipolar affective disorder and schizophrenia

“…Significant association has been reported between GABRAa5 markers and BPAD [Papadimitriou et al, 1998], unipolar disorder [Oruc et al, 1997], late onset (>25 years) schizophrenia [Papadimitriou et al, 2001a], and recently between a GABRAa3 marker and BPAD [Massat et al, 2002]. A recent mutation screen of GAD67 and haplotype association of unipolar depression has indicated that the GAD1 gene is not a major locus for predisposition to unipolar depression [Lappalainen et al, 2004].…”

GABA and Schizophrenia: A Review of Basic Science and Clinical Studies

“…This suggests common pathophysiological mechanisms underlying both affective disorders and schizophrenia, at least in a subgroup of patients. 83 On the other hand, postmortem schizophrenia studies have shown decreased benzodiazepine receptor (peripheral) density, a receptor mainly localized on glial cells, plays a role in neurosteroid synthesis, and increases with glial proliferation. Its DNA sequences in 11 Japanese schizophrenics showed one novel missense polymorphism (His162Arg) and another previously reported missense mutation (Ala147Thr).…”

New GABAA receptor alpha5 subunit gene polymorphism that may confound genotyping

“…This polymorphism was described by Glatt et al [1992] and the primers used for PCR amplification are: 5 0 -GATGACTTACCCACCTTTATTC-3 0 and 5 0 -GTAGAATTTCCCTGTAAAGGCAC-3 0 . Different alleles, with sizes between 272 and 292 bp, have been described [Glatt et al, 1992;Papadimitriou et al, 1998Papadimitriou et al, , 2001a. The most frequent in the general population are the 282, 284, 286, and 288 bp alleles.…”

“…After primer hybridization and PCR amplification, Glatt et al [1992] separated the different fragments by using 10% non-denaturing polyacrylamide gels. The same technique has been used by other authors who studied the association between this polymorphism and diseases such as bipolar disorder [Papadimitriou et al, 2001a,b], schizophrenia [Papadimitriou et al, 2001a], and panic disorder [Crowe et al, 1997].…”