Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia

Minori Koga, Hiroki Ishiguro, Saori Yazaki, Yasue Horiuchi, Makoto Arai, Kazuhiro Niizato, Shuji Iritani, Masanari Itokawa, Toshiya Inada, Nakao Iwata, Norio Ozaki, Hiroshi Ujike, Hiroshi Kunugi, Tsukasa Sasaki, Makoto Takahashi, Yuichiro Watanabe, Toshiyuki Someya, Akiyoshi Kakita, Hitoshi Takahashi, Hiroyuki NawaChristian Muchardt, Moshe Yaniv, Tadao Arinami

研究成果: Article査読

82 被引用数 (Scopus)

抄録

Chromatin remodeling may play a role in the neurobiology of schizophrenia and the process, therefore, may be considered as a therapeutic target. The SMARCA2 gene encodes BRM in the SWI/SNF chromatin-remodeling complex, and associations of single nucleotide polymorphisms (SNPs) to schizophrenia were found in two linkage disequilibrium blocks in the SMARCA2 gene after screening of 11 883 SNPs (rs2296212; overall allelic P = 5.8 × 10-5) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490; overall allelic P = 2.0 × 10-6) in a Japanese population. A risk allele of a missense polymorphism (rs2296212) induced a lower nuclear localization efficiency of BRM, and risk alleles of intronic polymorphisms (rs3763627 and rs3793490) were associated with low SMARCA2 expression levels in the postmortem prefrontal cortex. A significant correlation in the fold changes of gene expression from schizophrenic prefrontal cortex (from the Stanley Medical Research Institute online genomics database) was seen with suppression of SMARCA2 in transfected human cells by specific siRNA, and of orthologous genes in the prefrontal cortex of Smarca2 knockout mice. Smarca2 knockout mice showed impaired social interaction and prepulse inhibition. Psychotogenic drugs lowered Smarca2 expression while antipsychotic drugs increased it in the mouse brain. These findings support the existence of a role for BRM in the pathophysiology of schizophrenia.

本文言語English
ページ(範囲)2483-2494
ページ数12
ジャーナルHuman molecular genetics
18
13
DOI
出版ステータスPublished - 2009

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 遺伝学
  • 遺伝学(臨床)

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