Association of SNPs in EGR3 and ARC with schizophrenia supports a biological pathway for schizophrenia risk

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

Validation Phase: Comparison of Pooled Sample NGS with Individual Genotyping Results and Genetic Association Analyses in EU cohort.

<p><i>145 cases</i>, <i>150 controls; 195 males</i>, <i>100 females</i>.</p><p>Pooled EU.</p

Minor Allele Frequency Differences in EU and AA.

<p>Results of polymorphisms identified by NGS are mapped to the reference human genome used by the 1000 Genomes project (hg18). Vertical lines indicate the Δ MAF (difference between the minor allele frequency in cases versus controls) for each base pair of the genome region investigated. Higher peaks indicate a greater difference in prevalence of that variation between cases and controls, and thus a higher potential for association with schizophrenia risk. The red graph indicates data for Whites and the Blue graph indicates data for African Americans. (A) Δ MAF map for the <i>EGR3</i> locus, hg18 coordinates chr8:22,591,791–22,612,066. (B) Δ MAF map for the <i>ARC</i> locus, hg18 coordinates chr8:143,682,474–143,697,026</p

Validation Phase: Comparison of Pooled Sample NGS with Individual Genotyping Results and Genetic Association Analyses in AA cohort.

<p><i>42 cases</i>, <i>50 controls; 49 males</i>, <i>43 females</i>.</p><p>Pooled AA.</p

<i>ARC</i> SNP Association Analysis in All Populations Combined.

<p><i>1062 cases</i>, <i>691 controls; 1015 males</i>, <i>735 females</i>.</p><p>All Samples Combined <i>ARC</i>.</p

Replication Phase: Genetic Association Between Schizophrenia and SNPs in <i>EGR3</i> and <i>ARC</i> in AA Population.

<p><i>185 cases</i>, <i>50 controls; 127 males</i>, <i>108 females</i>.</p><p>Replication AA.</p

Replication of <i>ARC</i> SNP Association with Schizophrenia in Han Chinese Population.

<p><i>491 cases</i>, <i>491 controls; 525 males</i>, <i>457 females</i>.</p><p>Replication CH <i>ARC</i>.</p