Phenomic, convergent functional genomic, and biomarker studies in a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism

H. Le-Niculescu, M. J. McFarland, C. A. Ogden, Y. Balaraman, S. Patel, J. Tan, Z. A. Rodd, M. Paulus, M. A. Geyer, H. J. Edenberg, S. J. Glatt, S. V. Faraone, J. I. Nurnberger, R. Kuczenski, M. T. Tsuang, A. B. Niculescu

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

We had previously identified the clock gene D-box binding protein (Dbp) as a potential candidate gene for bipolar disorder and for alcoholism, using a Convergent Functional Genomics (CFG) approach. Here we report that mice with a homozygous deletion of DBP have lower locomotor activity, blunted responses to stimulants, and gain less weight over time. In response to a chronic stress paradigm, these mice exhibit a diametric switch in these phenotypes. DBP knockout mice are also activated by sleep deprivation, similar to bipolar patients, and that activation is prevented by treatment with the mood stabilizer drug valproate. Moreover, these mice show increased alcohol intake following exposure to stress. Microarray studies of brain and blood reveal a pattern of gene expression changes that may explain the observed phenotypes. CFG analysis of the gene expression changes identified a series of novel candidate genes and blood biomarkers for bipolar disorder, alcoholism, and stress reactivity.

Original languageEnglish (US)
Pages (from-to)134-166
Number of pages33
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume147
Issue number2
DOIs
StatePublished - Mar 5 2008

Keywords

  • Alcoholism
  • Biomarkers
  • Bipolar disorder
  • Brain
  • Clock gene
  • Genomics
  • Knockout
  • Mouse
  • Stress

ASJC Scopus subject areas

  • Genetics(clinical)
  • Neuropsychology and Physiological Psychology
  • Neuroscience(all)

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