Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity

Abstract

Excitement and controversy have followed neuregulin (NRG1) since its discovery as a putative schizophrenia susceptibility gene; however, the mechanism of action of the associated risk haplotype (HapICE) has not been identified, and specific genetic variations, which may increase risk to schizophrenia have remained elusive. Using a postmortem brain cohort from 37 schizophrenia cases and 37 controls, we resequenced upstream of the type I–IV promoters, and the HapICE repeat regions in intron 1. Relative abundance of seven NRG1 mRNA transcripts in the prefrontal cortex were determined and compared across diagnostic and genotypic groups. We identified 26 novel DNA variants and showed an increased novel variant load in cases compared with controls (χ2=7.815; P=0.05). The average nucleotide diversity (θ=10.0 × 10−4) was approximately twofold higher than that previously reported for BDNF, indicating that NRG1 may be particularly prone to genetic change. A greater nucleotide diversity was observed in the HapICE linkage disequilibrium block in schizophrenia cases (θ(case)=13.2 × 10−4; θ(control)=10.0 × 10−4). The specific HapICE risk haplotype was associated with increased type III mRNA (F=3.76, P=0.028), which in turn, was correlated with an earlier age of onset (r=−0.343, P=0.038). We found a novel intronic five-SNP haplotype ∼730 kb upstream of the type I promoter and determined that this region functions as transcriptional enhancer that is suppressed by SRY. We propose that the HapICE risk haplotype increases expression of the most brain-abundant form of NRG1, which in turn, elicits an earlier clinical presentation, thus providing a novel mechanism through which this genetic association may increase risk of schizophrenia.

Are There Schizophrenia Genetic Markers and Mutations? A Systematic Review and Meta-Analyses

“…This observation is consistent with their previous findings linking the schizophrenia-associated HAPICE risk haplotype [80] with increased NRG1-Type III mRNA expression [83], and their earlier observations of increased cytoplasmic NRG1-ICD in schizophrenia [77] [84].…”

Neuregulin-1 and schizophrenia in the genome-wide association study era

“…Several investigations of Nrg1 over-expression in mice have been carried out in response to evidence of elevated NRG1 expression (sometimes linked to genetic change in NRG1) in postmortem brains of patients with schizophrenia and bipolar disorder (Georgieva et al 2008;Hashimoto et al 2004;Weickert et al 2012). Many animal studies have focused on the type I Nrg1 isoform explored in the original study by Stefansson (Stefansson et al 2002), and suggest that NMDAR subunit phosphorylation (NR1/2) is not altered by type I over-expression in mice, at least not in early adulthood (8-12wks) Yin et al 2013).…”

“…However, no polymorphism has reached genome-wide significance (p=5 x 10 -8 ) 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.…”

Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

“…Several post-mortem studies indicated that both protein and mRNA levels of NRG1 isoforms and ErbB4 receptors are over-expressed in various brain regions of schizophrenia patients (although discrepancies exist) (Chong et al, 2008;Hashimoto et al, 2004;Law et al, 2007;Parlapani et al, 2010;Silberberg et al, 2006;Weickert et al, 2012). Weickert and colleagues (2012) also stated that HapICE risk alleles induced an earlier age of onset by increasing the mRNA expression of NRG1-type III, which indicates that the increased expression of NRG1 isoforms from post-mortem tissue is not a consequence of the disease or the drug treatment.…”