Kobayashi Momoko, Jitoku Daisuke, Iwayama Yoshimi, Yamamoto Naoki, Toyota Tomoko, Suzuki Katsuaki, Kikuchi Mitsuru, Hashimoto Tasuku, Kanahara Nobuhisa, Kurumaji Akeo, Yoshikawa Takeo, Nishikawa Toru
Department of Psychiatry and Behavioral Sciences, Graduate School of Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan.
PLoS One. 2018 Jan 8;13(1):e0190991. doi: 10.1371/journal.pone.0190991. eCollection 2018.
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.
多巴胺激动剂和N-甲基-D-天冬氨酸型谷氨酸受体拮抗剂所诱发的精神分裂症及精神分裂症样症状仅在青春期后出现。同样,这些药物所致的精神分裂症动物模型也是在出生后第三周左右的关键期之后诱发的。基于这些拟精神病效应的发育依赖性发病情况,我们利用DNA微阵列技术,将WD重复结构域3(WDR3)和壳二糖二磷酸二氢多萜醇β-甘露糖基转移酶(ALG1)基因鉴定为精神分裂症相关分子的新候选基因,其mRNA在成年(出生后第七周)大鼠中被间接多巴胺激动剂和N-甲基-D-天冬氨酸受体拮抗剂苯环利定上调,但在幼年(出生后第一周)大鼠中未上调。WDR3及其他相关蛋白是核蛋白,可能参与各种细胞活动,如细胞周期进程、信号转导、细胞凋亡和基因调控。ALG1据推测参与蛋白质N-糖基化的调控。为进一步阐明精神分裂症的分子病理生理学,我们评估了WDR3和ALG1在精神分裂症中的基因关联性。我们使用日本病例对照样本(1808例精神分裂症患者和2170例匹配对照)检测了这些基因的21个单核苷酸多态性[SNPs;W1(rs1812607)-W16(rs6656360),A1(rs8053916)-A10(rs9673733)]。未发现这些SNPs有显著的基因关联性。然而,我们在女性精神分裂症患者中检测到W4(rs319471)有显著关联性(等位基因P = 0.003,基因型P = 0.008)。基于单倍型分析,由W4(rs319471)-W5(rs379058)组成的观察到的单倍型在女性精神分裂症患者中也显示出显著关联性(P = 0.016)。即使在进行多重检验校正后这些关联性仍很显著。我们的研究结果表明,WDR3基因可能是女性精神分裂症患者的一个敏感因素,并且对WDR3信号通路的调节作为精神分裂症病理生理学的研究值得进一步探讨。