Thus, our results suggest the possibility that interaction between variants in NRG1 and ERBB4 might contribute to susceptibility for schizophrenia in a Japanese population.
The NRG1 status of 523 healthy subjects was determined with a single nucleotide polymorphism (SNP8NRG221533) which has been described as a tagging marker being part of the core at-risk haplotype for schizophrenia.
We hypothesise that variation in NRG1 may convey risk for schizophrenia by disrupting neural connectivity, possibly white matter integrity, and leading to a slower speed of cognitive processing.
Together, these results suggest that the molecular mechanism of the association between NRG1 risk alleles and schizophrenia may include down-regulation of nAChR alpha7 expression.
In this first study to select markers systematically on the basis of linkage disequilibrium across the entire NRG1 gene, we used haplotype-tagging single-nucleotide polymorphisms to identify single markers and haplotypes associated with schizophrenia and bipolar disorder in an independently ascertained Scottish population.
Using a B lymphoblast cell model, we previously demonstrated impairment in NRG1alpha-mediated migration in cells derived from patients with schizophrenia as well as effects of risk alleles in NRG1 and catechol-O-methyltransferase (COMT), a second gene implicated both in schizophrenia susceptibility and in cancer.
Our data suggest that type IV is a unique brain-specific NRG1 that is differentially expressed and processed during early development, is translated, and its expression regulated by a schizophrenia risk-associated functional promoter or single nucleotide polymorphism (SNP).
We review the structure and functions of NRG1, consider the evidence for and against it being a schizophrenia susceptibility gene, and discuss mechanisms that might underlie the contribution of NRG1 to disease pathophysiology.
This meta-analysis supports the involvement of NRG1 in the pathogenesis of schizophrenia, but with association between two different but adjacent haplotypes blocks in the Caucasian and Asian populations.
NRG1-induced suppression of NMDA receptor activation was more pronounced in schizophrenia subjects than in controls, consistent with enhanced NRG1-erbB4 signaling seen in this illness.
Although the samples size is relatively small, the findings support a role for NRG1 in SZ in African Americans and suggest that polymorphic differences in regions of the gene that recognize AT-binding proteins may be a factor in disease pathogenesis.
Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with erbB4, and that genetic interaction between variants at the two loci increases susceptibility to schizophrenia.