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

PLoS One. 2018 Jan 8;13(1):e0190991. doi: 10.1371/journal.pone.0190991. eCollection 2018.

Abstract

Schizophrenia and schizophrenia-like symptoms induced by the dopamine agonists and N-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 (WDR3) and chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1) 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 N-glycosylation. To further elucidate the molecular pathophysiology of schizophrenia, we have evaluated the genetic association of WDR3 and ALG1 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 P = 0.003, genotypic P = 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 (P = 0.016). Even after correction for multiple testing, these associations remained significant. Our findings suggest that the WDR3 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Epistasis, Genetic
  • Female
  • Humans
  • Japan
  • Male
  • Mannosyltransferases / genetics*
  • Middle Aged
  • Nuclear Proteins / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide
  • Schizophrenia / genetics

Substances

  • Nuclear Proteins
  • WDR3 protein, human
  • Mannosyltransferases
  • chitobiosyldiphosphodolichol beta-mannosyltransferase

Grants and funding

Toru Nishikawa received the grant entitled “Strategic Research Program for Brain Sciences” funded by the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Daisuke Jitoku received the grant named “Grant-in-Aid for Scientific Research (C) (No. 24791202)” funded by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.