Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation

Hum Mol Genet. 2006 Jun 15;15(12):1949-62. doi: 10.1093/hmg/ddl118. Epub 2006 May 10.

Abstract

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 eight genes (RAP1GA1, SST, HLA-DRA, KATNB1, PURA, NDUFV2, STAR and PAFAH1B3) in a bipolar-specific manner and one gene (CCL3) which was downregulated 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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism
  • Algorithms
  • Bipolar Disorder / genetics*
  • Bipolar Disorder / physiopathology*
  • Case-Control Studies
  • DNA-Binding Proteins / genetics
  • Gene Expression Profiling*
  • Genome, Human
  • HLA-DR Antigens / genetics
  • HLA-DR alpha-Chains
  • Humans
  • NADH Dehydrogenase / genetics
  • Neural Pathways
  • Oligonucleotide Array Sequence Analysis
  • Parietal Lobe / physiopathology*
  • Polymorphism, Single Nucleotide
  • Prefrontal Cortex / physiopathology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Schizophrenia / genetics
  • Somatostatin / genetics
  • Transcription Factors / genetics
  • rap1 GTP-Binding Proteins / genetics
  • rap1 GTP-Binding Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • HLA-DR Antigens
  • HLA-DR alpha-Chains
  • PURA protein, human
  • Transcription Factors
  • Somatostatin
  • NADH Dehydrogenase
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • rap1 GTP-Binding Proteins
  • NDUFV2 protein, human