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.

Conclusion: 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.

Figure 1

Binding specificities of ErbB receptor family ligands. EGF (epidermal growth factor), AREG (amphiregulin) and TGFA (transforming growth factor-α) bind EGFR (ErbB1) only. BTC (Betacellulin), HBEGF (heparin-binding EGF-like growth factor) and EREG (Epiregulin) bind EGFR and ErbB4. NRG1 and NRG2 bind ErbB3 and ErbB4. NRG3 and NRG4 are specific for ErbB4. Receptors form homo- and heterodimers after ligand-binding (not shown). As indicated (X), ErbB2 has no ligand-binding capacity and ErbB3 has no active kinase domain. Only NRG1-4 and ERBB1-4 genes were investigated in this study. (Modified from [46]).

Figure 2

Genotypic single-point association test results and LD over NRG1. In the plot of -log₁₀(P) v. map position, horizontal dashed lines are at P = 0.05, 0.01 and 0.001. Vertical dashed lines are at 20 kb intervals. The region covered by the gene is indicated in the centre of the figure by a horizontal line, with an arrow head indicating the direction of transcription. A crossing vertical line indicates the position of each exon. At the base of the figure, LD between SNP loci is indicated by shading. White: r² = 0; black: r² = 1.

Figure 3

Genotypic single-point association test results and LD over ERBB4. In the plot of -log₁₀(P) v. map position, horizontal dashed lines are at P = 0.05, 0.01 and 0.001. Vertical dashed lines are at 20 kb intervals. The region covered by the gene is indicated in the centre of the figure by a horizontal line, with an arrow head indicating the direction of transcription. A crossing vertical line indicates the position of each exon. At the base of the figure, LD between SNP loci is indicated by shading. White: r² = 0; black: r² = 1.

Figure 4

Genotypic single-point association test results and LD over NRG2, NRG3, EGFR and ERBB2. In the plot of -log₁₀(P) v. map position, horizontal dashed lines are at P = 0.05, 0.01 and 0.001. Vertical dashed lines are at 20 kb intervals. The region covered by the gene is indicated in the centre of the figure by a horizontal line, with an arrow head indicating the direction of transcription. A crossing vertical line indicates the position of each exon.

Figure 5

Distribution of the types of pair-wise interaction in gene combinations with a large percentage of significant interactions. The total in each column corresponds to the number of significant interactions presented in Table 3, i.e. the numerator of the fraction presented in that table for the gene combination in question.