Meta-analysis reveals associations between genetic variation in the 5′ and 3′ regions of Neuregulin-1 and schizophrenia

Abstract

Genetic, post-mortem and neuroimaging studies repeatedly implicate neuregulin-1 (NRG1) as a critical component in the pathophysiology of schizophrenia. Although a number of risk haplotypes along with several genetic polymorphisms in the 5′ and 3′ regions of NRG1 have been linked with schizophrenia, results have been mixed. To reconcile these conflicting findings, we conducted a meta-analysis examining 22 polymorphisms and two haplotypes in NRG1 among 16 720 cases, 20 449 controls and 2157 family trios. We found significant associations for three polymorphisms (rs62510682, rs35753505 and 478B14-848) at the 5′-end and two (rs2954041 and rs10503929) near the 3′-end of NRG1. Population stratification effects were found for the rs35753505 and 478B14-848(4) polymorphisms. There was evidence of heterogeneity for all significant markers and the findings were robust to publication bias. No significant haplotype associations were found. Our results suggest genetic variation at the 5′ and 3′ ends of NRG1 are associated with schizophrenia and provide renewed justification for further investigation of NRG1’s role in the pathophysiology of schizophrenia.

Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice

“…Third, mutating NRG1 and ErbB4 or altering their levels in mice could recapitulate SZ-related endophenotypes (3,18,24,(46)(47)(48). Finally, recent meta-analyses (49)(50)(51), including one from 2017 on >16,000 schizophrenic patients and >20,000 controls (49), identify NRG1 and ErbB4 as risk genes for SZ. Interestingly, SNP rs7598440 of ErbB4 could predict cortical or cerebrospinal fluid GABA concentration in healthy human subjects (52,53), in agreement with critical roles of ErbB4 in the development and function of the GABA circuitry from mouse studies.…”

Translating advances in the molecular basis of schizophrenia into novel cognitive treatment strategies

“…NRG1 and disrupted in schizophrenia 1 ( DISC1 )] is whether this genomic evidence is sufficiently robust to exclude such genes from further investigation, despite continually robust meta‐analytic data in terms of individual genes (e.g. NRG1 , Mostaid et al, ), or whether biological plausibility should be taken into account when evaluating the potential of a gene target to inform on the biological basis of schizophrenia and/or antipsychotic drug discovery (see Porteous et al, ; Farrell et al, ; Harrison, ). In the context of drug discovery, important considerations include whether the gene target implicated is already associated with a known biochemical pathway implicated in schizophrenia, as well as immediate therapeutic tractability where genes encoding receptors, ion channels, among others, are more attractive targets than non‐protein encoding genes, genes of unknown function or genes which are predominantly expressed and implicated in early brain development (Harrison, ).…”

“…Multiple promoter usage and abundant alternative splicing has produced several distinct isoforms of the NRG1 gene, which have been classified into a minimum of seven subtypes (types I–VI; Mei and Xiong, ). NRG1 is a schizophrenia susceptibility gene that has been linked with the pathogenesis of schizophrenia (Munafò et al, ; Gong et al, ; Mostaid et al, ). Post‐mortem brain and serum‐based analyses from schizophrenia cases have demonstrated both increased NRG1 signalling and up‐regulation of specific NRG1/erb‐B2 receptor tyrosine kinase 4 (ErbB4) splice variants (Hahn et al, ; Law et al, , ; Chong et al, ) or decreased isoform‐specific expression of NRG1 transcripts (Parlapani et al, ).…”

Proteolytic Processing of Neuregulin 2

“…Nonetheless, the impaired growth rate is compensated over the course of four months and Nrg2-KO mice become indistinguishable from control mice [10]. Alteration of NRG1 expression or genetic polymorphism in Nrg1 gene are linked to the pathophysiology of schizophrenia [11,12]. Single nucleotide polymorphism analysis and association studies also pointed to a genome region encompassing NRG2 locus to be Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-019-01846-9) contains supplementary material, which is available to authorized users.…”