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.