Neuregulin 1 and Susceptibility to Schizophrenia

Abstract

The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

“…22 Finally, mouse models with disruptions in NRG1-ERBB4 signaling appear to capture some of the behavioral phenotypes associated with schizophrenia, and in certain cases these altered behaviors can be ameliorated by antipsychotics. 1,[23][24][25] Altogether, the data support a role for abnormal NRG1-ERB signaling in schizophrenia. Dissecting the pathways of NRG1-ERB signaling in the central nervous system may therefore contribute to the elucidation of pathways of schizophrenia susceptibility and may also reveal targets for interventions.…”

“…[1][2][3][4] NRG1 spans a 1.4-megabase region of chromosome 8p13, and is comprised of at least 20 exons. The gene undergoes complex alternative splicing, generating at least 15 protein isoforms that fall into six families (identified as I-VI).…”

Extreme population differences across Neuregulin 1 gene, with implications for association studies

“…9,[23][24][25][26][27][28][29]52 Two of the five SNPs defining the at-risk haplotype previously reported 9 were included in this study, SNPnrg2 and SNPnrg4. These two SNPs plus three additional ones typed in this study were located in the area of Hap ICE .…”

“…4,8 These factors along with possible genetic heterogeneity have complicated efforts to date aimed at elucidating the underlying genetic basis of this debilitating brain disorder. One of the most exciting candidate genes to come out of these studies in recent years is Neuregulin 1 (NRG1), which was first implicated in a genome wide scan in an Icelandic population by Stefansson et al 9 The chromosomal region where NRG1 is located, 8p12-p21, corresponds with an area previously identified as a schizophrenia susceptibility locus (SCZD6) by a number of earlier studies, although these failed to localise the gene involved. 8,[10][11][12] NRG1 is a very long 1.4 Mb gene with a large number of structurally and functionally distinct isoforms produced by alternative splicing.…”

“…13,[15][16][17][18] NRG1 is also involved in the glutamatergic pathway; the involvement of this system in schizophrenia development is one of the most prominent neurochemical hypothesis proposed to explain the biological component of this disease. 7,[19][20][21][22] In the Stefansson et al 9 study of NRG1, a number of overlapping haplotypes were shown to be significantly over-represented in patients compared to controls. These 'at-risk' haplotypes, all shared a common 'core' consisting of five SNPs and two microsatellite markers, the so-called Hap ICE , and extended a length of 290 kb from the 5 0 end of the GGF2 variant of the NRG1 and into the first exon of this splice form (see Figure 1).…”