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Phenomic, Convergent Functional Genomic, and biomarker studies in a stress‐reactive genetic animal model of bipolar disorder and co‐morbid alcoholism
Author(s) -
LeNiculescu H.,
McFarland M.J.,
Ogden C.A.,
Balaraman Y.,
Patel S.,
Tan J.,
Rodd Z.A.,
Paulus M.,
Geyer M.A.,
Edenberg H.J.,
Glatt S.J.,
Faraone S.V.,
Nurnberger J.I.,
Kuczenski R.,
Tsuang M.T.,
Niculescu A.B.
Publication year - 2008
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.30707
Subject(s) - bipolar disorder , phenotype , microarray , candidate gene , biomarker , gene , microarray analysis techniques , knockout mouse , gene knockout , gene expression , mood , genetics , biology , medicine , psychiatry
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. © 2008 Wiley‐Liss, Inc.