The involvement of ErbB4 with schizophrenia: association and expression studies.
Neuregulin 1 (NRG1) has been found to be associated with schizophrenia in several populations. Consistently, mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. These observations raised the hypothesis that impaired NRG1-ErbB4 signaling may contribute to schizophrenia susceptibility. Nineteen SNPs encompassing the ErbB4 gene were selected from the HapMap database and genotyped in genomic DNA isolated from 59 Ashkenazi schizophrenia patients and 130 matched controls. Expression analysis of ErbB4 splice variants was performed on postmortem DLPFC samples obtained from Caucasian patients and controls by real-time PCR. We found a highly significant difference between patient and control groups in three SNPs from one linkage disequilibrium (LD) block both in allele (P = 0.013, 0.0045, 0.0049) and genotype frequencies (P = 0.00013, 0.000021, 0.00018), as well as a risk haplotype (P = 0.00044). Expression analysis indicated that the CYT-1 isoform is overexpressed in patients (P = 0.047) and that juxtamembrane (JM)-a displays a similar trend (P = 0.081). This study provides a direct link between ErbB4 and the disease. We propose that NRG1 and its receptor ErbB4 are components of a biological pathway, involved in the pathophysiology of schizophrenia.
Silberberg
Gilad
G
Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Darvasi
Ariel
A
Pinkas-Kramarski
Ronit
R
Navon
Ruth
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4; D012559:Schizophrenia / Q000235:genetics*
D020033:Protein Isoforms; D012333:RNA, Messenger; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4