Human Molecular Genetics Advance Access originally published online on April 10, 2009
Human Molecular Genetics 2009 18(13):2483-2494; doi:10.1093/hmg/ddp166
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia
1 Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan 2 CREST, Japan Science and Technology Agency, Kawaguchi-shi, Saitama 332-0012, Japan 3 Department of Schizophrenia Research, Tokyo Institute of Psychiatry, Tokyo 156-8585, Japan 4 Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, Tokyo 156-0057, Japan 5 Institute of Neuropsychiatry, Seiwa Hospital, Tokyo 162-0851, Japan 6 Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan 7 Department of Psychiatry, School of Medicine, Nagoya University, Nagoya 466-8550, Aichi, Japan 8 Department of Neuropsychiatry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan 9 Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan 10 Office for Mental Health Support and Graduate School of Education, University of Tokyo, Tokyo 113-0033, Japan 11 Department of Psychiatry, Niigata University Graduate School of Medical and Denatal Sciences, Niigata 951-8510, Japan 12 Brain Research Institute, Niigata University, Niigata 951-8585, Japan 13 Unit of Epigenetic Regulation, Avenir INSERM, URA2578 CNRS, Fernbach Bldg. Institut Pasteur, 25, rue du Dr-Roux 75724, Paris Cedex 15, France
* To whom correspondence should be addressed at: Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan. Tel: +81 298533177; Fax: +81 298533333; Email: tarinami{at}md.tsukuba.ac.jp
Received November 28, 2008; Revised March 26, 2009; Accepted April 2, 2009
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 x 10–5) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490; overall allelic P = 2.0 x 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.