title: Interactions among genes in the ErbB-Neuregulin signalling network are associated with increased susceptibility to schizophrenia.
abstract: BACKGROUND
  Evidence of genetic association between the NRG1 (Neuregulin-1) gene and schizophrenia is now well-documented. Furthermore, several recent reports suggest association between schizophrenia and single-nucleotide polymorphisms (SNPs) in ERBB4, one of the receptors for Neuregulin-1. In this study, we have extended the previously published associations by investigating the involvement of all eight genes from the ERBB and NRG families for association with schizophrenia.
  
  
  METHODS
  Eight genes from the ERBB and NRG families were tested for association to schizophrenia using a collection of 396 cases and 1,342 blood bank controls ascertained from Aberdeen, UK. A total of 365 SNPs were tested. Association testing of both alleles and genotypes was carried out using the fast Fisher's Exact Test (FET). To understand better the nature of the associations, all pairs of SNPs separated by >or= 0.5 cM with at least nominal evidence of association (P < 0.10) were tested for evidence of pairwise interaction by logistic regression analysis.
  
  
  RESULTS
  42 out of 365 tested SNPs in the eight genes from the ERBB and NRG gene families were significantly associated with schizophrenia (P < 0.05). Associated SNPs were located in ERBB4 and NRG1, confirming earlier reports. However, novel associations were also seen in NRG2, NRG3 and EGFR. In pairwise interaction tests, clear evidence of gene-gene interaction was detected for NRG1-NRG2, NRG1-NRG3 and EGFR-NRG2, and suggestive evidence was also seen for ERBB4-NRG1, ERBB4-NRG2, ERBB4-NRG3 and ERBB4-ERBB2. Evidence of intragenic interaction was seen for SNPs in ERBB4.
  
  
  CONCLUSIONS
  These new findings suggest that observed associations between NRG1 and schizophrenia may be mediated through functional interaction not just with ERBB4, but with other members of the NRG and ERBB families. There is evidence that genetic interaction among these loci may increase susceptibility to schizophrenia.
authors.affiliation: Psychiatry CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW Harlow, Essex, UK. Isabel.M.Benzel@gsk.com
authors.forename: Isabel
authors.initials: I
authors.lastname: Benzel
authors.forename: Aruna
authors.initials: A
authors.lastname: Bansal
authors.forename: Brian L
authors.initials: BL
authors.lastname: Browning
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Galwey
authors.forename: Peter R
authors.initials: PR
authors.lastname: Maycox
authors.forename: Ralph
authors.initials: R
authors.lastname: McGinnis
authors.forename: Devi
authors.initials: D
authors.lastname: Smart
authors.forename: David
authors.initials: D
authors.lastname: St Clair
authors.forename: Phillip
authors.initials: P
authors.lastname: Yates
authors.forename: Ian
authors.initials: I
authors.lastname: Purvis