Human Molecular Genetics Advance Access published online on May 10, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl118
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1 Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan,
* To whom correspondence should be addressed. The limited number of genome-wide transcriptome analyses using the postmortem brains of bipolar disorder sufferers has not produced a clear consensus on the molecular pathways affected by the disorder.To expand the knowledge in this area, we examined the expression levels of more than 12,000 genes in Brodmann's Area (BA) 46 (dorsolateral prefrontal cortex) from bipolar I disorder and control samples using Affymetrix GeneChips. This analysis detected 108 differentially expressed genes in bipolar brains. Validation studies using quantitative RT-PCR on the two original diagnostic cohorts plus tissue from schizophrenic subjects, confirmed the differential expressions of 8 genes (RAP1GA1, SST, HLA-DRA, KATNB1, PURA, NDUFV2, STAR, and PAFAH1B3) in a bipolar-specific manner and one gene (CCL3) which was down-regulated in both bipolar and schizophrenic brains. Of these, protein levels of RAP1GA1 (RAP1 GTPase activating protein 1) showed a trend of increase in BA46 from bipolar brains, in keeping with mRNA transcript levels. Transmission disequilibrium analysis of the nine genes using 43 single nucleotide polymorphisms (SNPs) in 229 National Institute of Mental Health (NIMH) bipolar trios exposed nominal SNP association and modest empirical haplotypic association (P = 0.033) between SST (somatostatin) and disease. Finally, gene network analysis using the currently obtained expression data highlighted cellular growth and nervous system development pathways as potential targets in the molecular pathophysiology of bipolar disorder.
Received March 7, 2006
Revised April 28, 2006
Accepted April 28, 2006
Article
Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation
Noriaki Nakatani 1,
Eiji Hattori 1,
Tetsuo Ohnishi 1,
Brian Dean 2,
Yoshimi Iwayama 1,
Izuru Matsumoto 3,
Tadafumi Kato 4,
Noriko Osumi 5,
Teruhiko Higuchi 6,
Shin-ichi Niwa 7,
and
Takeo Yoshikawa 8 *
2 The Rebecca L. Cooper Research Laboratories, Mental Health Research Institute of Victoria, Parkville Victoria 3052, Australia,
3 Department of Pathology, The University of Sydney, NSW 2006, Australia
4 Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama 351-0198, Japan
5 Division of Developmental Neuroscience, Center for Translational and Advanced Animal Research, Tohoku University School of Medicine, Miyagi 980-8575, Japan,; CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan
6 Musashi Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan
7 Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan
8 Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan,; CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan
Takeo Yoshikawa, E-mail: takeo{at}brain.riken.jp
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