title: Assessment of copy number variations in the brain genome of schizophrenia patients.
abstract: BACKGROUND
  Cytogenomic mutations and chromosomal abnormality are implicated in the neuropathology of several brain diseases. Cell ﻿heterogeneity of brain tissues makes their detection and validation difficult, however. In the present study, we analyzed gene dosage alterations in brain DNA of schizophrenia patients and compared those with the copy number variations (CNVs) identified in schizophrenia patients as well as with those in Asian lymphocyte DNA and attempted to obtain hints at the pathological contribution of cytogenomic instability to schizophrenia.
  
  
  RESULTS
  Brain DNA was extracted from postmortem striatum of schizophrenia patients and control subjects (n = 48 each) and subjected to the direct two color microarray analysis that limits technical data variations. Disease-associated biases of relative DNA doses were statistically analyzed with Bonferroni's compensation on the premise of brain cell mosaicism. We found that the relative gene dosage of 85 regions significantly varied among a million of probe sites. In the candidate CNV regions, 26 regions had no overlaps with the common CNVs found in Asian populations and included the genes (i.e., ANTXRL, CHST9, DNM3, NDST3, SDK1, STRC, SKY) that are associated with schizophrenia and/or other psychiatric diseases. The majority of these candidate CNVs exhibited high statistical probabilities but their signal differences in gene dosage were less than 1.5-fold. For test evaluation, we rather selected the 10 candidate CNV regions that exhibited higher aberration scores or larger global effects and were thus confirmable by PCR. Quantitative PCR verified the loss of gene dosage at two loci (1p36.21 and 1p13.3) and confirmed the global variation of the copy number distributions at two loci (11p15.4 and 13q21.1), both indicating the utility of the present strategy. These test loci, however, exhibited the same somatic CNV patterns in the other brain region.
  
  
  CONCLUSIONS
  The present study lists the candidate regions potentially representing cytogenomic CNVs in the brain of schizophrenia patients, although the significant but modest alterations in their brain genome doses largely remain to be characterized further.
authors.affiliation: Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757, Asahimachi-dori, 951-8585 Niigata, Japan ; Department of Psychiatry, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, 951-8510 Niigata, Japan.
authors.forename: Miwako
authors.initials: M
authors.lastname: Sakai
authors.affiliation: Department of Psychiatry, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, 951-8510 Niigata, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Psychiatry, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, 951-8510 Niigata, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Someya
authors.affiliation: Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757, Asahimachi-dori, 951-8585 Niigata, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Araki
authors.affiliation: Department of Psychiatry, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, 951-8510 Niigata, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Shibuya
authors.affiliation: Matsuzawa Hospital, Setagaya-ku, 156-0057 Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Niizato
authors.affiliation: Matsuzawa Hospital, Setagaya-ku, 156-0057 Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Oshima
authors.affiliation: Departments of Neuropsychiatry, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Kunii
authors.affiliation: Departments of Neuropsychiatry, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan.
authors.forename: Hirooki
authors.initials: H
authors.lastname: Yabe
authors.affiliation: Departments of Neuropsychiatry, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Matsumoto
authors.affiliation: Departments of Neuropsychiatry, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Wada
authors.affiliation: Departments of Neuropsychiatry, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Hino
authors.affiliation: Division of Psychiatry and Neurology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Hyogo Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Division of Psychiatry and Neurology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Hyogo Japan.
authors.forename: Akitoyo
authors.initials: A
authors.lastname: Hishimoto
authors.affiliation: Division of Psychiatry and Neurology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Hyogo Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Kitamura
authors.affiliation: Matsuzawa Hospital, Setagaya-ku, 156-0057 Tokyo, Japan ; Department of Mental Health, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Aichi Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Iritani
authors.affiliation: Division of Psychiatry and Neurology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Hyogo Japan ; Department of Neuropsychiatry, Kinki University Faculty of Medicine, 589-8511 Osaka-Sayama, Osaka Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Shirakawa
authors.affiliation: Division of Psychiatry and Neurology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Hyogo Japan ; Department of Social Rehabilitation, Kobe University School of Medicine, 654-0142 Hyogo, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Department of Molecular Genetics, Brain Research Institute, Niigata University, 951-8585 Niigata, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Miyashita
authors.affiliation: Departments of Neuropsychiatry, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Niwa
authors.affiliation: Pathology and Brain Disease Research Center, Brain Research Institute, Niigata University, 951-8585 Niigata, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Pathology and Brain Disease Research Center, Brain Research Institute, Niigata University, 951-8585 Niigata, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.affiliation: Department of Molecular Genetics, Brain Research Institute, Niigata University, 951-8585 Niigata, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Kuwano
authors.affiliation: Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757, Asahimachi-dori, 951-8585 Niigata, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nawa
keywords: CNV; Caudate; Genome instability; Schizophrenia; Somatic mutation