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.
Highlights
Neuregulin-1 (NRG1) is a pleiotropic growth factor involved in circuitry generation, axon ensheathment, neuronal migration, synaptic plasticity, myelination and neurotransmission.[1,2,3,4]
Research to date has focused on the 5′-region of NRG1. This 5′bias has been driven by the landmark study in 2002 conducted by Stefansson et al.,[7] who identified a seven-marker schizophreniaassociated haplotype in the Icelandic population (HapICE) consisting of five single-nucleotide polymorphisms (SNPs) and two microsatellites (478B14-848 and 420M9-1395) in the 5′-region of NRG1
For a study to be included in the meta-analysis, the following criteria were required: (a) a case–control or family-based genetic association studies investigating one or more SNPs and/or microsatellites of NRG1; (b) published in peer-reviewed journal containing original data; (c) included clinically diagnosed schizophrenia patients using an accepted classification system; and (d) provided sufficient genotype or allelic data for calculation of an odds ratio (OR)
Summary
Neuregulin-1 (NRG1) is a pleiotropic growth factor involved in circuitry generation, axon ensheathment, neuronal migration, synaptic plasticity, myelination and neurotransmission.[1,2,3,4] it is centrally involved in neurodevelopment and signalling in the mature central nervous system, where it exerts its actions through binding to its cognate receptor tyrosine kinases, ErbB3 and ErbB4, members of the epidermal growth factor system. Research to date has focused on the 5′-region of NRG1 This 5′bias has been driven by the landmark study in 2002 conducted by Stefansson et al.,[7] who identified a seven-marker schizophreniaassociated haplotype in the Icelandic population (HapICE) consisting of five SNPs and two microsatellites (478B14-848 and 420M9-1395) in the 5′-region of NRG1. As this milestone study, additional 5′-schizophrenia-associated haplotypes in the Irish (HapIRE)[8] and Chinese (HapChina1-3)[9] populations have been identified. We have conducted an updated comprehensive meta-analysis of the association between NRG1 genetic variation and schizophrenia, including single markers across the entire gene as well as haplotypes
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