Schizophrenia is not associated with the functional candidate gene ERBB3: results from a case-control study

Increasing evidence has supported the hypothesis of a neurodevelopmental component in the etiology of schizophrenia. Recently, several independent microarray gene expression studies have revealed downregulated expression of myelin-related genes in the postmortem brains of schizophrenia patients. Complete myelination of the cortex has been observed to occur in late adolescence and early adulthood, which is typically the age of onset of schizophrenia. ERBB3 is a gene which has not only been found to be downregulated in schizophrenia simultaneously in three microarray studies, but also is a strong candidate because of its potential role in neurodevelopment as a receptor of NRG1. Therefore, we performed association analysis of seven nonsynonymous SNPs in this gene. Two SNPs in ERBB3 (rs773123 and rs2271188) were polymorphic in our samples, neither of which showed significant evidence of association with the illness (P = 0.639 and 0.561, respectively). Because replication across such studies is notoriously difficult, the microarray evidence implicating ERBB3 still strongly supports some role of this gene in schizophrenia. However, our failure to find genetic association suggests that the differential expression of ERBB3 in schizophrenia may be environmentally driven, or involve cis- or trans-acting genetic factors beyond the boundaries of the gene itself.