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

Helen Le-Niculescu, M. J. McFarland, C. A. Ogden, Y. Balaraman, S. Patel, J. Tan, Zachary Rodd, M. Paulus, M. A. Geyer, Howard Edenberg, S. J. Glatt, S. V. Faraone, John Nurnberger, R. Kuczenski, M. T. Tsuang, Alexander Niculescu

Research output: Contribution to journalArticle

82 Citations (Scopus)

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
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

Fingerprint

Genetic Models
Bipolar Disorder
Alcoholism
Animal Models
Biomarkers
Genomics
Genes
Phenotype
Gene Expression
Patient Participation
Sleep Deprivation
Valproic Acid
Locomotion
Knockout Mice
Weight Gain
Carrier Proteins
Alcohols
Brain
Pharmaceutical Preparations
Therapeutics

Keywords

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

ASJC Scopus subject areas

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

Cite this

Phenomic, convergent functional genomic, and biomarker studies in a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism. / Le-Niculescu, Helen; McFarland, M. J.; Ogden, C. A.; Balaraman, Y.; Patel, S.; Tan, J.; Rodd, Zachary; Paulus, M.; Geyer, M. A.; Edenberg, Howard; Glatt, S. J.; Faraone, S. V.; Nurnberger, John; Kuczenski, R.; Tsuang, M. T.; Niculescu, Alexander.

In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, Vol. 147, No. 2, 05.03.2008, p. 134-166.

Research output: Contribution to journalArticle

Le-Niculescu, Helen ; McFarland, M. J. ; Ogden, C. A. ; Balaraman, Y. ; Patel, S. ; Tan, J. ; Rodd, Zachary ; Paulus, M. ; Geyer, M. A. ; Edenberg, Howard ; Glatt, S. J. ; Faraone, S. V. ; Nurnberger, John ; Kuczenski, R. ; Tsuang, M. T. ; Niculescu, Alexander. / Phenomic, convergent functional genomic, and biomarker studies in a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism. In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. 2008 ; Vol. 147, No. 2. pp. 134-166.
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