Assessment of copy number variations in the brain genome of schizophrenia patients

Molecular Cytogenetics

Hiroyuki Nawa³  Ryozo Kuwano⁶  Akiyoshi Kakita¹  Hitoshi Takahashi¹  Shin-ichi Niwa^1,10  Akinori Miyashita⁶  Kiyoshi Maeda⁷  Osamu Shirakawa⁹  Shuji Iritani⁵  Noboru Kitamura⁴  Akitoyo Hishimoto⁴  Takeshi Hashimoto⁴  Mizuki Hino^1,10  Akira Wada^1,10  Junya Matsumoto^1,10  Hirooki Yabe^1,10  Yasuto Kunii^1,10  Kenichi Oshima⁸  Kazuhiro Niizato⁸  Masako Shibuya²  Kazuaki Araki³  Toshiyuki Someya²  Yuichiro Watanabe²  Miwako Sakai² 

[1] Pathology and Brain Disease Research Center, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan;Department of Psychiatry, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Niigata, 951-8510, Japan;Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757, Asahimachi-dori, Niigata, 951-8585, Japan;Division of Psychiatry and Neurology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Hyogo, Japan;Department of Mental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Aichi, Japan;Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan;Department of Social Rehabilitation, Kobe University School of Medicine, Hyogo, 654-0142, Japan;Matsuzawa Hospital, Setagaya-ku, Tokyo, 156-0057, Japan;Department of Neuropsychiatry, Kinki University Faculty of Medicine, Osaka-Sayama, 589-8511, Osaka, Japan;Departments of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan

关键词: Somatic mutation;    Schizophrenia;    Genome instability;    Caudate;    CNV;   

Others  :  1221595
DOI  :  10.1186/s13039-015-0144-5

 received in 2015-03-09, accepted in 2015-05-12,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Sakai et al.

【 图 表 】

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