Review articleNeuregulin-1 and schizophrenia in the genome-wide association study era
Introduction
Neuregulin-1 (NRG1) is one of the most extensively studied genes in schizophrenia. The genomic region surrounding NRG1 first attracted attention following linkage analyses (Brzustowicz et al., 1999, Gurling et al., 2001, Kendler et al., 1996, Pulver et al., 1995) implicating a locus on chromosome 8p21-22 with the disorder. Subsequent fine mapping and linkage disequilibrium analysis in Icelandic patients led to the discovery of a haplotype (HAPICE) associated with schizophrenia and a parallel preclinical study showed NRG1 hypomorphic (i.e. reduced gene expression) mice had a reduction in N-methyl-d-aspartate receptors (NMDAR) in forebrain areas and deficits in prepulse inhibition of the startle response compared to wild-type mice (Stefansson et al., 2002). This seminal work generated a tremendous amount of enthusiasm when published and remains one of the cornerstones of NRG1 research in schizophrenia to date. However, no polymorphism has reached genome-wide significance (p = 5 ÿ 108) in any genome-wide association study (GWAS) in schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics, 2014), despite the inclusion of 400 or more NRG1 SNPs and gene coverage within the upper 10% of all protein-coding genes included on conventional GWAS platforms (Lehne et al., 2011). This suggests that the absence of a NRG1 signal in GWAS is unlikely to be a result of poor SNP coverage but rather a result of allelic heterogeneity at the NRG1 locus (Weickert et al., 2012), which in large samples is likely to result in a loss of a genetic signal. Nevertheless, this absence of GWAS support has attenuated enthusiasm for future NRG1 research and has questioned the relevance of NRG1 in schizophrenia.
Relevance of a gene to a particular disorder however, should not be determined exclusively on whether nucleotide variation within it meets genome-wide significance but rather on the whole of the evidence base. As such, we have completed a comprehensive assessment of the last decade of clinical research into the relationship between NRG1 and schizophrenia (for a review of the research prior to 2006 see: Harrison and Law, 2006). In addition, we provide a targeted review of preclinical studies that have examined NRG1s effects on excitatory and inhibitory neurotransmission as recent preclinical reviews (Lisman, 2012, Mei and Nave, 2014) have not covered this topic thoroughly and an imbalance of excitatory/inhibitory transmission is one of several putative neurobiological mechanisms of schizophrenia (Chana et al., 2013). We conclude with recommendations for future research that we hope will help prioritize a strategy forward to further advance our understanding of the relationship between NRG1 and schizophrenia.
Section snippets
NRG1 structure and isoforms
NRG1 spans 1.125 megabases and comprises more than 20 exons as well as several large introns from which over 30 splice isoforms can be produced that are grouped into six types (IVI) (Fig. 1). NRG1 types I and II contain an immunoglobulin (Ig) like domain, encoded by exons E178 and E122 respectively. This Ig region is also present in types IV and V and, together (I, II, IV and V) are commonly defined as Ig-NRG1. The Ig domain is linked to the epidermal growth factor (EGF) like domain with or
NRG1 and excitatory/inhibitory neurotransmission
A putative imbalance of excitatory/inhibitory transmission in the cortex, striatum and hippocampus is one likely neurobiological underpinning of schizophrenia (Carlsson and Carlsson, 1990). Current theories suggest that in schizophrenia excitatory activity of pyramidal neurons may be blunted in frontal brain regions (Stone et al., 2007) responsible for attention, memory and other executive functions, but overactive in the hippocampus (Grace, 2012, Schobel et al., 2013) and in certain
Family studies
The original family study in the Icelandic population linking a haplotype (HAPICE) in the 5⿲ region of NRG1 with schizophrenia (Stefansson et al., 2002) stimulated numerous additional family studies of which seven were conducted in the past decade (Table 4; for details on family studies from 2002 to 2005 see: Harrison and Law, 2006). Unlike the family studies conducted soon after the Icelandic study, the ancestral backgrounds of cohorts in more recent studies have been diverse, covering
Human post-mortem brain mRNA studies
Seven NRG1 gene expression studies using human post-mortem brain tissue have been published, six in the past decade (Table 6). Four of these studies have used case-control and the other three control only designs. Among the case-control studies, the first was conducted in 2004 (Hashimoto et al., 2004) using dorsolateral prefrontal cortex (DLPFC) tissue (20 schizophrenia, 19 controls) and noted an increase in type I NRG1 gene expression in schizophrenia. This finding has since been replicated in
NRG1 protein expression studies
Studies of NRG1 protein levels in schizophrenia have been hampered by the lack of specific antibodies for a majority of the NRG1 isoforms and methodological variations across studies. Despite these limitations, six post-mortem brain, one serum, and one plasma study in humans have been published (Table 7). Two studies have reported on NRG1α, one reporting a decrease in PFC white matter (Bertram et al., 2007) and the other no difference in Brodmanns area 46 (frontal cortex) (Boer et al., 2009).
Structural neuroimaging studies
In the past decade, twelve studies have examined the association between NRG1 genetic variation and brain structure (Table 8). These studies have in large part taken a region of interest approach and have almost exclusively selected polymorphisms within the HAPICE. The SNP8NRG221533 polymorphism has received the most attention (6 studies). The C risk allele at this locus was associated with lower white matter volume (detected with voxel based morphometry) in the regions of the right uncinate
NRG1 and antipsychotic treatment response
The association between NRG1 genetic variation on antipsychotic response was first reported in a study of 94 Finnish individuals with schizophrenia taking typical antipsychotics for a minimum of four weeks (Kampman et al., 2004). In this study, homozygotes of the non-risk T allele at the SNP8NRG221533 (rs35753505) locus were over-represented in the non-responder group. Interestingly, a decade has passed since this study but to our knowledge, only two additional studies examining NRG1 genetic
Future directions
Throughout our review we have noted a number of gaps and limitations within the current NRG1 literature that warrant future study. To guide this future clinical and preclinical work and assist in prioritizing a strategy forward we have generated the following recommendations:
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Look beyond the central dogma. Human-based evidence related to the epigenetic (e.g. methylation), post-transcriptional (e.g. microRNA), or post-translational (e.g. phosphorylation, ubiquitination, cleavage) modification of
Summary
The past decade of clinical research and recent preclinical findings clearly show that the link between NRG1 and schizophrenia is complex and will require further concerted and collaborative efforts to be elucidated. At the preclinical level, there is strong evidence that Nrg1 may disrupt normal excitatory/inhibitory neurotransmission via the ErbB4 receptor, potentially mediated by downstream effects such as gamma oscillations that then interfere with cognitive processes principally involving
Acknowledgements
MM was supported by a Cooperative Research Centre for Mental Health Top-up Scholarship. SS and AP were supported by One-in-Five Association Incorporated. CP was supported by an NHMRC Senior Principal Research Fellowship (#628386), and a Brain and Behavior Research Foundation (NARSAD) Distinguished Investigator Award. TK is supported by a Career Development Fellowship (Level 2: #1045643) and a project grant (#1102012) from the National Health and Medical Research Council (NHMRC), as well as the
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