Association studies of WD repeat domain 3 and chitobiosyldiphosphodolichol beta-mannosyltransferase genes with schizophrenia in a Japanese population

<div><p>Schizophrenia and schizophrenia-like symptoms induced by the dopamine agonists and <i>N</i>-methyl-D aspartate type glutamate receptor antagonists occur only after the adolescent period. Similarly, animal models of schizophrenia by these drugs are also induced after the critical period around postnatal week three. Based upon the development-dependent onsets of these psychotomimetic effects, by using a DNA microarray technique, we identified the WD repeat domain 3 (<i>WDR3</i>) and chitobiosyldiphosphodolichol beta-mannosyltransferase (<i>ALG1</i>) genes as novel candidates for schizophrenia-related molecules, whose mRNAs were up-regulated in the adult (postnatal week seven), but not in the infant (postnatal week one) rats by an indirect dopamine agonist, and phencyclidine, an antagonist of the NMDA receptor. WDR3 and other related proteins are the nuclear proteins presumably involved in various cellular activities, such as cell cycle progression, signal transduction, apoptosis, and gene regulation. ALG1 is presumed to be involved in the regulation of the protein <i>N</i>-glycosylation. To further elucidate the molecular pathophysiology of schizophrenia, we have evaluated the genetic association of <i>WDR3</i> and <i>ALG1</i> in schizophrenia. We examined 21 single nucleotide polymorphisms [SNPs; W1 (rs1812607)-W16 (rs6656360), A1 (rs8053916)-A10 (rs9673733)] from these genes using the Japanese case-control sample (1,808 schizophrenics and 2,170 matched controls). No significant genetic associations of these SNPs were identified. However, we detected a significant association of W4 (rs319471) in the female schizophrenics (allelic <i>P</i> = 0.003, genotypic <i>P</i> = 0.008). Based on a haplotype analysis, the observed haplotypes consisting of W4 (rs319471)–W5 (rs379058) also displayed a significant association in the female schizophrenics (<i>P</i> = 0.016). Even after correction for multiple testing, these associations remained significant. Our findings suggest that the <i>WDR3</i> gene may likely be a sensitive factor in female patients with schizophrenia, and that modification of the WDR3 signaling pathway warrants further investigation as to the pathophysiology of schizophrenia.</p></div

Genomic structure of human <i>WDR3</i> and <i>ALG1</i>.

<p>Genomic structures and positions of the SNPs in human <i>WDR3</i> (A) and <i>ALG1</i> (B). Exons are denoted by boxes with untranslated regions in gray, and translated regions in white. SNPs denoted in light blue are located in the CTCF binding site, and in green are the tag SNPs (correlation coefficient: r²>0.85, minor allele frequency: MAF>0.10).</p

Block-based haplotype analysis of <i>WDR3</i> and <i>ALG1</i> genes.

<p>Block-based haplotype analysis of <i>WDR3</i> and <i>ALG1</i> genes.</p

LD block structure of <i>WDR3</i> and <i>ALG1</i> genes.

<p>(A) <i>WDR3</i> gene consists of three, and (B) <i>ALG1</i> gene consists of two haplotype blocks in schizophrenia. In the left panel, the number in the box represents D’ (×100), blank means D’ = 1. In the right panel, the number in the box represents r² (×100).</p

Power estimation of case-control sample and classified groups.

<p>Power estimation of case-control sample and classified groups.</p

The MDR analysis for the best determined model.

<p>The MDR analysis for the best determined model.</p

SNP information for <i>WDR3</i> and <i>ALG1</i> genes.

<p>SNP information for <i>WDR3</i> and <i>ALG1</i> genes.</p

Sex stratified block-based haplotype analysis of <i>WDR3</i> and <i>ALG1</i> genes.

<p>Sex stratified block-based haplotype analysis of <i>WDR3</i> and <i>ALG1</i> genes.</p

Genotyping and allele distribution of SNPs on <i>WDR3</i> and <i>ALG1</i> genes in schizophrenia and controls from the Japanese population.

<p>Genotyping and allele distribution of SNPs on <i>WDR3</i> and <i>ALG1</i> genes in schizophrenia and controls from the Japanese population.</p