Candidate genes, pathways and mechanisms for alcoholism: An expanded convergent functional genomics approach

Zachary Rodd, B. A. Bertsch, W. N. Strother, Helen Le-Niculescu, Y. Balaraman, E. Hayden, R. E. Jerome, L. Lumeng, John Nurnberger, Howard Edenberg, W. J. McBride, Alexander Niculescu

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

We describe a comprehensive translational approach for identifying candidate genes for alcoholism. The approach relies on the cross-matching of animal model brain gene expression data with human genetic linkage data, as well as human tissue data and biological roles data, an approach termed convergent functional genomics. An analysis of three animal model paradigms, based on inbred alcohol-preferring (iP) and alcohol-non-preferring (iNP) rats, and their response to treatments with alcohol, was used. A comprehensive analysis of microarray gene expression data from five key brain regions (frontal cortex, amygdala, caudate-putamen, nucleus accumbens and hippocampus) was carried out. The Bayesian-like integration of multiple independent lines of evidence, each by itself lacking sufficient discriminatory power, led to the identification of high probability candidate genes, pathways and mechanisms for alcoholism. These data reveal that alcohol has pleiotropic effects on multiple systems, which may explain the diverse neuropsychiatric and medical pathology in alcoholism. Some of the pathways identified suggest avenues for pharmacotherapy of alcoholism with existing agents, such as angiotensin-converting enzyme (ACE) inhibitors. Experiments we carried out in alcohol-preferring rats with an ACE inhibitor show a marked modulation of alcohol intake. Other pathways are new potential targets for drug development. The emergent overall picture is that physical and physiological robustness may permit alcohol-preferring individuals to withstand the aversive effects of alcohol. In conjunction with a higher reactivity to its rewarding effects, they may able to ingest enough of this nonspecific drug for a strong hedonic and addictive effect to occur.

Original languageEnglish
Pages (from-to)222-256
Number of pages35
JournalPharmacogenomics Journal
Volume7
Issue number4
DOIs
StatePublished - Aug 2007

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Genomics
Alcoholism
Alcohols
Genes
Angiotensin-Converting Enzyme Inhibitors
Animal Models
Gene Expression
Genetic Linkage
Pleasure
Caudate Nucleus
Putamen
Nucleus Accumbens
Medical Genetics
Brain
Frontal Lobe
Microarray Analysis
Amygdala
Pharmaceutical Preparations
Hippocampus
Pathology

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Genetics

Cite this

Candidate genes, pathways and mechanisms for alcoholism : An expanded convergent functional genomics approach. / Rodd, Zachary; Bertsch, B. A.; Strother, W. N.; Le-Niculescu, Helen; Balaraman, Y.; Hayden, E.; Jerome, R. E.; Lumeng, L.; Nurnberger, John; Edenberg, Howard; McBride, W. J.; Niculescu, Alexander.

In: Pharmacogenomics Journal, Vol. 7, No. 4, 08.2007, p. 222-256.

Research output: Contribution to journalArticle

Rodd, Zachary ; Bertsch, B. A. ; Strother, W. N. ; Le-Niculescu, Helen ; Balaraman, Y. ; Hayden, E. ; Jerome, R. E. ; Lumeng, L. ; Nurnberger, John ; Edenberg, Howard ; McBride, W. J. ; Niculescu, Alexander. / Candidate genes, pathways and mechanisms for alcoholism : An expanded convergent functional genomics approach. In: Pharmacogenomics Journal. 2007 ; Vol. 7, No. 4. pp. 222-256.
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