Abstract
We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 x 10−7; OR [95% CI] = 1.54 [1.310–1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes.
Highlights
Schizophrenia is a severe mental illness that affects approximately 1% of the world’s population and is determined by both genetic and environmental factors [1, 2]
The early growth response gene (EGR) family of Immediate early gene (IEG) transcription factors is involved in numerous neural processes, including regulation of synaptic proteins and synaptic plasticity, dysfunction of which have been hypothesized to play a role in schizophrenia pathogenesis [4,5,6,7,8,9,10]
To identify variations within the EGR3 and ARC loci that have a high likelihood for association with schizophrenia risk in two different racial groups, we used a two-step approach
Summary
Schizophrenia is a severe mental illness that affects approximately 1% of the world’s population and is determined by both genetic and environmental factors [1, 2]. The remaining influence may be attributed to environmental factors [2]. How environmental exposures interact with genetic variations to influence schizophrenia susceptibility remains unclear. Immediate early gene (IEG) transcription factors are rapidly activated in the brain in response to environmental stimuli and regulate downstream neuronal gene expression. The early growth response gene (EGR) family of IEG transcription factors is involved in numerous neural processes, including regulation of synaptic proteins and synaptic plasticity, dysfunction of which have been hypothesized to play a role in schizophrenia pathogenesis [4,5,6,7,8,9,10]
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