Schizophrenia is a complex psychiatric disease with a strong genetic predisposition. Linkage and association studies in different ethnic populations implicate Neuregulin 1 (NRG1) as a candidate susceptibility gene for schizophrenia. NRG1 functions by interacting with ErbB tyrosine kinase receptors and plays a critical role in neuronal migration and differentiation and central nervous system development. NRG1-ErbB signaling could lead to a variety of abnormal neurodevelopmental events that have been implicated in the underlying pathology of schizophrenia. Here we show in a cell-model system, that B lymphoblasts migrate to NRG1 through the ErbB-signaling system as observed in neuronal cells. We assessed NRG1-induced cell migration in B lymphoblasts from patients with schizophrenia and found that NRG1-induced migration is significantly decreased compared with control individuals in 2 independent cohorts. The magnitude of NRG1-induced migration is associated with polymorphisms of the NRG1 and catechol-o-methyltransferase (COMT) genes and with an epistatic interaction of these genes. Our findings confirmed that the functional COMT Val/Met polymorphism does in fact influence NRG1-mediated cell migration. The COMT enzyme, which is responsible for dopamine catabolism has been shown to influence cortical dopaminergic signaling and function, presumably since dopamine transporters are relatively scarce in this region. Consistent with the hypothesis that Val is a risk allele, the subjects carrying the Val/Val genotype evinced significantly lower NRG1-mediated migration compared with those carrying Met/Met alleles. Moreover, severe defects in NRG1-stimulated phosphorylation of AKT were observed at least in some Val/Val subjects. These results suggest a novel biological effect of COMT potentially related to schizophrenia pathogenesis, and indicate an epistatic interaction of these genes at a biological level. It is generally assumed that multiple genes interact with each other and with the environment to account for the risk architecture of schizophrenia, but to our knowledge, this is the first demonstration of biologic epistasis between putative schizophrenia risk genes. This study demonstrated the migratory response of schizophrenia-derived cells to NRG1 is impaired and is associated with genetic variations in more than one schizophrenia susceptibility gene, providing a novel insight into potential neurodevelopmental mechanisms of schizophrenia. If common genes shared by neuronal cells and lymphocytes regulate NRG1-induced migration, this suggest that NRG1-mediated neural migration may be abnormal in patients with schizophrenia during development. Although controversial, aberrant neuronal migration has been suspected from reports of cytoarchitectural abnormalities in the cortex of patients with schizophrenia. Thus, our findings suggest a potential molecular pathway involved in the neurodevelopmental origins of schizophrenia.? ? Metabotropic glutamate receptor 3 (GRM3) is an important regulator of synaptic glutamate. We report the existence of 3 splice variants, resulting from exon skipping events, of GRM3 in human brain. Interestingly, these splice variants are expressed in prefrontal cortex, hippocampus, cerebellum and lymphoblasts. The most abundant GRM3 variant lacks exon 4 (GRM34) is human brain and B lymphoblasts specific. The existence of the GRM34 isoform is important due to the association of non-coding single nucleotide polymorphisms in GRM3 with schizophrenia and as a potential therapeutic target for several neuropsychiatric disorders
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