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

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.