Genetic Analysis of the relationship between NRG, ErbB and Schizophrenia
Schizophrenia is a devastating psychiatric disease that affects 0.5-1% of the world wide adult population. Genetic linkage studies have provided strong evidence that neuregulin-1 (NRG1) is a candidate susceptibility gene for schizophrenia in many populations of diverse ethnicities. Neuregulins are cell-cell signalling proteins that are ligands for receptor tyrosine kinases of the ErbB family. Further evidence that implicates Nrg-1 and ErbB4 (a neuronal receptor for Nrg-1) in schizophrenia was provided by NRG1 and ERBB4 heterozygous knock-out mice, which display phenotypes observed in schizophrenia animal models. Furthermore, Nrg-1-ErbB signalling is involved in many biological processes that have a potential role in the pathophysiology of the disease. A test for association of schizophrenia and schizoaffective disorder with the NRG and ErbB gene families (NRG1-4, ErbB1-4) was performed using 365 genetic markers. The test population comprised 396 Scottish Caucasian subjects with a diagnosis of schizophrenia or schizoaffective disorder according to the Operational Criteria Checklist (OPCRIT) for psychotic and affective illness, and 1342 control subjects. Seventy-nine genetic markers in 6 of the candidate genes showed evidence of association with susceptibility to schizophrenia or schizoaffective disorder in an allelic or genotypic test at the p≤0.10 significance level. From this set of 79 markers, all pairs of markers at least 0.5cM apart were tested using the logistic regression interaction analysis for effects that modulate susceptibility to schizophrenia. Four gene combinations gave substantially more significant pair-wise interactions than were expected by chance. These were NRG1-NRG2, NRG1-NRG3, ErbB1-NRG2 and intra-gene SNP combinations in ErbB4. These results provide some support for the hypothesis that pairs of markers in one or more candidate genes interact to confer or diminish susceptibility to schizophrenia. These genes are candidates for further confirmatory investigation.