The <i>DAO</i> Gene Is Associated with Schizophrenia and Interacts with Other Genes in the Taiwan Han Chinese Population

<div><p>Background</p><p>Schizophrenia is a highly heritable disease with a polygenic mode of inheritance. Many studies have contributed to our understanding of the genetic underpinnings of schizophrenia, but little is known about how interactions among genes affect the risk of schizophrenia. This study aimed to assess the associations and interactions among genes that confer vulnerability to schizophrenia and to examine the moderating effect of neuropsychological impairment.</p> <p>Methods</p><p>We analyzed 99 SNPs from 10 candidate genes in 1,512 subject samples. The permutation-based single-locus, multi-locus association tests, and a gene-based multifactorial dimension reduction procedure were used to examine genetic associations and interactions to schizophrenia.</p> <p>Results</p><p>We found that no single SNP was significantly associated with schizophrenia. However, a risk haplotype, namely <i>A</i>-<i>T</i>-<i>C</i> of the SNP triplet rsDAO7-rsDAO8-rsDAO13 of the <i>DAO</i> gene, was strongly associated with schizophrenia. Interaction analyses identified multiple between-gene and within-gene interactions. Between-gene interactions including <i>DAO</i>*<i>DISC1</i><b>,</b><i>DAO</i>*<i>NRG1</i> and <i>DAO</i>*<i>RASD2</i> and a within-gene interaction for <i>CACNG2</i> were found among schizophrenia subjects with severe sustained attention deficits, suggesting a modifying effect of impaired neuropsychological functioning. Other interactions such as the within-gene interaction of <i>DAO</i> and the between-gene interaction of <i>DAO</i> and <i>PTK2B</i> were consistently identified regardless of stratification by neuropsychological dysfunction. Importantly, except for the within-gene interaction of <i>CACNG2</i>, all of the identified risk haplotypes and interactions involved SNPs from <i>DAO</i>.</p> <p>Conclusions</p><p>These results suggest that <i>DAO</i>, which is involved in the N-methyl-d-aspartate receptor regulation, signaling and glutamate metabolism, is the master gene of the genetic associations and interactions underlying schizophrenia. Besides, the interaction between <i>DAO</i> and <i>RASD2</i> has provided an insight in integrating the glutamate and dopamine hypotheses of schizophrenia.</p> </div

A schematic diagram to show the relation among genes that involved in the observed gene-gene interactions.

<p>The top, bottom, and left side components represent the pre-synaptic neuron, post-synaptic neuron, and glial cells, respectively. Three types of receptors (NMDA receptor, ERBB4 receptor, and AMPA receptor) are drawn on the post-synaptic neuron. All the genes involved in the gene-gene interactions are shown in boldface. <i>NRG1</i> is the ligand for ERBB4 receptor, which may trigger the long term potentiation by way of the <i>PTK2B</i> protein activation. <i>DISC1</i> may stabilize serine racemase (SR), which will convert L-Serine to d-Serine (d-Ser). The black triangle on the side of NMDA receptor represents d-Ser, which is a co-agonist of this receptor. Both NMDA and AMPA receptors are calcium channels, which may increase calcium influx upon activation. Two molecules of <i>CACNG2</i> (shown by the grey oval) were found on each AMPA receptor. Even though <i>CACNG2</i> is a subunit of AMPA receptor, this protein is explicitly drawn in order to show its role in gene-gene interaction.</p

Within-gene and between-gene interactions in schizophrenia for the unstratified and CPT-stratified interaction analyses.

<p>The unstratified interaction plot is at the center, and the CPT-stratified plots with the stratum name are located in the four corners. Stratum name and sample size of cases and controls are provided in the title for each panel. Gene name, the number of SNPs in the gene, and the located chromosome are provided around each circle. If an interaction was identified, the SNP id along with its location in the gene (in parentheses) are provided. Abbreviations for SNP locations are: 3′, 3′ untranslated region; 5′, 5′ untranslated region; I, intron; E, exon; s, synonymous SNP; n, near-gene SNP; m, missense SNP. Interaction candidates with a pFDR <0.05 and ≥0.05 are connected by a solid line and dashed line, respectively, and the level of testing accuracy is represented by the line color from light green (less accurate) to dark green (highly accurate).</p

The LD structures of 84 SNPs in 10 candidate genes for vulnerability to schizophrenia.

<p>For each gene, the id of each SNP in the gene is listed, and the locations reflect the relative physical positions of the SNPs (in units of base pairs). The LD coefficient, D’, is provided unless D’ = 1. The color scheme for D’ presentation is as follows: white depicts the case of D’ <1 and LOD <2; blue depicts the case of D’ = 1 and LOD <2; pink or light red depicts the case of D’ <1 and LOD ≥2; bright red depicts the case of D’ = 1 and LOD ≥2. The LD block(s) within each gene is marked by an inverted triangle based on Gabriel’s method <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060099#pone.0060099-Gabriel1" target="_blank">[81]</a>.</p