Medical Genetics Section, Centre for Molecular Medicine and Institute of Genetics and Molecular Medicine, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
Schizophrenia (SCZ) and bipolar disorder (BPD) are severe heritable psychiatric disorders involving a complex genetic aetiology. Neuregulin 1 (NRG1) is a leading candidate gene for SCZ, and has recently been implicated in BPD. We previously reported association of two NRG1 haplotypes with SCZ and BPD in a Scottish case-control sample. One haplotype is located at the 5' end of the gene (region A), and the other is located at the 3' end (region B). Here, association to haplotypes within regions A and B was assessed in patients with SCZ and BPD in a second Scottish case-control sample and in the two Scottish samples combined. Association to region B was also assessed in patients with SCZ and BPD in a German case-control sample, and in all three samples combined. No evidence was found for association in the new samples when analysed individually; however, in the joint analysis of the two Scottish samples, a region B haplotype comprising two SNPs (rs6988339 and rs3757930) was associated with SCZ and the combined case group (SCZ: p=0.0037, OR=1.3, 95% CI: 1.1-1.6; BPD+SCZ: p=0.0080, OR=1.2, 95% CI: 1.1-1.5), with these associations withstanding multiple testing correction at the single-test level (SCZ: p(st)=0.022; BPD+SCZ: p(st)=0.044). This study supports the involvement of NRG1 variants in the less well studied 3' region in conferring susceptibility to SCZ and BPD in the Scottish population.
"A number of genetic loci were consistently found to be associated with schizophrenia. Genes of the major histocompatibility complex (MHC) region on chromosome 6p21.3–22.1 (de Jong et al., 2012; Li et al., 2010; Shi et al., 2009; Stefansson et al., 2009; Wright et al., 1996), the zinc finger protein gene ZNF804A on chromosome 2q32.1 (Hill and Bray, 2012; Kuswanto et al., 2012; Ripke et al., 2011; Williams et al., 2011; Zhang et al., 2011), neuregulin1 (NRG1) on chromosome 8 (Agim et al., 2013; Li et al., 2006; Stefansson et al., 2009; Walker et al., 2010), and transcription factor 4 (TCF4) on chromosome 18q21.2 (Blake et al., 2010; Li et al., 2010; Navarrete et al., 2013; Stefansson et al., 2009) were consistently found to be associated with schizophrenia. "
"Accumulating evidence from human genetic studies suggests that multiple susceptibility genes or loci, including Neuregulin 1 (NRG1) (Schwab and Wildenauer, 2009), might contribute to the pathogenesis of schizophrenia. The association between NRG1 and schizophrenia was initially revealed in a study of families in Iceland (Stefansson et al., 2002), and the association has been further confirmed in other ethnic groups (Walker et al., 2010). Reduced levels of the expression of NRG1 have also been reported in schizophrenic post-mortem tissues (Bertram et al., 2007; Nicodemus et al., 2009; Parlapani et al., 2010), which indicates that alterations in NRG1 might contribute to the pathophysiology of schizophrenia. "
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, neural plasticity, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 is abundantly expressed in the hippocampus, and emerging studies have begun to reveal the link between NRG1 signaling and cognitive deficits in schizophrenic patients. Because the transmembrane domain of NRG1 is vital for both forward and reverse signaling cascades, new Nrg1-deficient mice that carry a truncation of the transmembrane domain of the Nrg1 gene were characterized and used in this study to test a NRG1 loss-of-function hypothesis for schizophrenia. Both male and female Nrg1 heterozygous mutant mice and their wild-type littermates were used in a series of 4 experiments to characterize the impact of Nrg1 on behavioral phenotypes and to determine the importance of Nrg1 in the regulation of hippocampal neuromorphology and local GABAergic interneurons. First, a comprehensive battery of behavioral tasks indicated that male Nrg1-deficient mice exhibited significant impairments in cognitive functions. Second, pharmacological challenges were conducted and revealed that Nrg1 haploinsufficiency altered GABAergic activity in males. Third, although no genotype-specific neuromorphological alterations were found in the hippocampal CA1 pyramidal neurons, significant reductions in the hippocampal expressions of GAD67 and parvalbumin were revealed in the Nrg1-deficient males. Fourth, chronic treatment with valproate rescued the observed behavioral deficits and hippocampal GAD67 reduction in Nrg1-deficient males. Collectively, these results indicate the potential therapeutic effect of valproate and the importance of Nrg1 in the regulation of cognitive functions and hippocampal GABAergic interneurons, especially in males.
"(DISC1) [e.g., Hodgkinson et al., 2004], neuregulin 1 [e.g., Green et al., 2005; Walss-Bass et al., 2006; Walker et al., 2010], and ZNF804A [e.g., Williams et al., 2011] also show significant association with BPD provide increasing support for the possibility of shared biological pathways across the SCZ–BPD continuum. A recent genome-wide association study (GWAS) of a collaborative European case-control sample found that common polygenic variation contributes to risk for both SCZ and BPD [Purcell et al., 2009]. "
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.