Systematic study of association of four GABAergic genes: glutamic acid decarboxylase 1 gene, glutamic acid decarboxylase 2 gene, GABA(B) receptor 1 gene and GABA(A) receptor subunit beta2 gene, with schizophrenia using a universal DNA microarray.
Several studies have suggested the dysfunction of the GABAergic system as a risk factor in the pathogenesis of schizophrenia. In the present study, case-control association analysis was conducted in four GABAergic genes: two glutamic acid decarboxylase genes (GAD1 and GAD2), a GABA(A) receptor subunit beta2 gene (GABRB2) and a GABA(B) receptor 1 gene (GABBR1). Using a universal DNA microarray procedure we genotyped a total of 20 SNPs on the above four genes in a study involving 292 patients and 286 controls of Chinese descent. Statistically significant differences were observed in the allelic frequencies of the rs187269C/T polymorphism in the GABRB2 gene (P=0.0450, chi(2)=12.40, OR=1.65) and the -292A/C polymorphism in the GAD1 gene (P=0.0450, chi(2)=14.64 OR=1.77). In addition, using an electrophoretic mobility shift assay (EMSA), we discovered differences in the U251 nuclear protein binding to oligonucleotides representing the -292 SNP on the GAD1 gene, which suggests that the -292C allele has reduced transcription factor binding efficiency compared with the 292A allele. Using the multifactor-dimensionality reduction method (MDR), we found that the interactions among the rs187269C/T polymorphism in the GABRB2 gene, the -243A/G polymorphism in the GAD2 gene and the 27379C/T and 661C/T polymorphisms in the GAD1 gene revealed a significant association with schizophrenia (P<0.001). These findings suggest that the GABRB2 and GAD1 genes alone and the combined effects of the polymorphisms in the four GABAergic system genes may confer susceptibility to the development of schizophrenia in the Chinese population.
Zhao
Xu
X
Bio-X Life Science Research Center, Shanghai Jiao Tong University, Hao Ran Building, Shanghai 200030, China.
Qin
Shengying
S
Shi
Yongyong
Y
Zhang
Aiping
A
Zhang
Jing
J
Bian
Li
L
Wan
Chunling
C
Feng
Guoyin
G
Gu
Niufan
N
Zhang
Guangqi
G
He
Guang
G
He
Lin
L
D000328:Adult; D044466:Asian People / Q000235:genetics* / Q000523:psychology; D016022:Case-Control Studies; D002681:China; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015870:Gene Expression / Q000502:physiology; D005787:Gene Frequency; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A / Q000235:genetics*; D018080:Receptors, GABA-B / Q000235:genetics*; D012559:Schizophrenia / Q000208:ethnology / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C495710:GABRB2 protein, human; D005819:Genetic Markers; D007527:Isoenzymes; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2