Association analysis of the glutamic acid decarboxylase 2 and the glutamine synthetase genes (GAD2, GLUL) with schizophrenia.
OBJECTIVE
As dysfunction of glutamatergic neurotransmission is one of the plausible hypotheses for the pathogenesis of schizophrenia, genes involved in the glutamate neurotransmitter system are candidates for schizophrenia susceptibility. The aim of this study is to clarify the contribution of two genes encoding glutamate metabolic enzymes: the glutamic acid decarboxylase 2 gene (GAD2) and the glutamine synthetase gene (GLUL), in schizophrenia.


METHODS
We genotyped 300 Japanese schizophrenia patients and 300 healthy controls for 14 single nucleotide polymorphisms (SNPs) in GAD2 (approximately 91 kb in size) and six SNPs in GLUL (approximately 14 kb in size). We examined 'single-point' association as well as pairwise haplotype association for all SNPs with schizophrenia.


RESULTS
We observed no significant 'single-point' associations with the disease in any of the 20 SNPs after correction for multiple testing using False Discovery Rate. We also observed no significant haplotype associations with False Discovery Rate. Furthermore, we analyzed gene-gene interactions, including six glutamate receptor genes we have reported previously in the association studies of GRIA4, GRIN2D, GRIK3, GRIK4, GRIK5, and GRM3, using the multifactor dimensionality reduction method. The best interaction model, however, did not show the statistical significance.


CONCLUSIONS
These results suggest that GAD2 and GLUL do not play a major role in schizophrenia pathogenesis and there is no gene-gene interaction between the eight genes in the Japanese population.
Arai
Shinsaku
S
Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Shibata
Hiroki
H
Sakai
Mayumi
M
Ninomiya
Hideaki
H
Iwata
Nakao
N
Ozaki
Norio
N
Fukumaki
Yasuyuki
Y
D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000235:genetics*; D005974:Glutamate-Ammonia Ligase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000201:enzymology* / Q000235:genetics*
D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D005974:Glutamate-Ammonia Ligase