Genetic and functional analyses of early growth response (EGR) family genes in schizophrenia.
OBJECTIVE
Early growth response genes (EGR1, 2, 3, and 4) encode a family of nuclear proteins that function as transcriptional regulators. They are involved in the regulation of synaptic plasticity, learning, and memory, and are implicated in the pathogenesis of schizophrenia.


METHODS
We conducted a genetic association analysis of 14 SNPs selected from the EGR1, 2, 3, and 4 genes of 564 patients with schizophrenia and 564 control subjects. We also conducted Western blot analysis and promoter activity assay to characterize the EGR genes associated with schizophrenia


RESULTS
We did not detect a true genetic association of these 14 SNPs with schizophrenia in this sample. However, we observed a nominal over-representation of C/C genotype of rs9990 of EGR2 in female schizophrenia as compared to female control subjects (p=0.012, uncorrected for multiple testing). Further study showed that the average mRNA level of the EGR2 gene in the lymphoblastoid cell lines of female schizophrenia patients was significantly higher than that in female control subjects (p=0.002). We also detected a nominal association of 4 SNPs (rs6747506, rs6718289, rs2229294, and rs3813226) of the EGR4 gene that form strong linkage disequilibrium with schizophrenia in males. Reporter gene assay showed that the haplotype T-A derived from rs6747506 and rs6718289 at the promoter region had significantly reduced promoter activity compared with the haplotype A-G.


CONCLUSIONS
Our data suggest a tendency of gender-specific association of EGR2 and EGR4 in schizophrenia, with an elevated expression of EGR2 in lympoblastoid cell lines of female schizophrenia patients and a reduced EGR4 gene expression in male schizophrenia patients.
Department of Psychiatry, Yuli Mental Health Research Center, Yuli Veterans Hospital, Hualien, Taiwan.
Min-Chih
MC
Cheng
Yang-An
YA
Chuang
Chao-Lin
CL
Lu
Yu-Jung
YJ
Chen
Sy-Ueng
SU
Luu
Jun-Ming
JM
Li
Shih-Hsin
SH
Hsu
Chia-Hsiang
CH
Chen
D000328:Adult; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D051765:Early Growth Response Transcription Factors / Q000235:genetics*; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods / Q000706:statistics & numerical data; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D012727:Sex Characteristics
D051765:Early Growth Response Transcription Factors