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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.

Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk