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

Scatter plot of MMP-9 serum levels in patients with MDD and healthy controls.

<p>Serum levels of MMP-9 in patients with MDD did not differ from those of normal controls.</p

Demographic data of subjects.

<p>Data show the mean ± SD. Figures in parenthesis represent the range.</p><p>WHOQOL-BREF: World Health Organization Quality of Life-Short Version.</p><p>SASS: Social Adaptation Self-evaluation Scale, SIGH-D: 17 items of the Structured Interview Guide for the Hamilton Depression Rating Scale.</p>*<p>Student's t-test, ⁺Mann-Whitney's U-test.</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

Relationships between MMP-9 serum levels and clinical variables in patients with MDD.

<p>(A): There was a significant negative correlation (ρ = −0.366, p = 0.002) between MMP-9 serum levels and WHOQOL-BREF scores. (B): There was a significant negative correlation (ρ = −0.355, p = 0.003) between MMP-9 serum levels and SASS scores. (C): There was a significant positive correlation (ρ = 0.397, p = 0.001) between MMP-9 serum levels and the SIGH-D score.</p

Scatter plot of proBDNF and mature BDNF serum levels in patients with MDD and healthy controls.

<p>(A): Serum levels of proBDNF in 20 patients with MDD and 29 healthy subjects were below the minimum detectable concentration (0.5 ng/mL) of the proBDNF ELISA kits. Serum levels of proBDNF in patients with MDD did not differ from those of normal controls. (B): In contrast, serum levels (21.09±5.60 ng/mL) of mature BDNF in patients with MDD, were significantly lower than those (23.11±5.90 ng/mL) of normal controls.</p

Power estimation of case-control sample and classified groups.

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

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

Relationships between clinical variables in patients with MDD.

<p>(A): There was a significant negative correlation (r = −0.705, p<0.001) between the SIGH-D score and WHOQOL-BREF score in patients. (B): There was a significant negative correlation (r = −0.579, p<0.001) between the SIGH-D and SASS scores in patients. (C): There was a positive correlation (r = 0.404, p = 0.001) between the CogState composite score and QOL score in patients. (D): There was a positive correlation (r = 0.371, p = 0.002) between the CogState composite score and SASS score in patients.</p

The MDR analysis for the best determined model.

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