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

The Pharmacogenomics Journal volume 7, pages 222–256 (2007)Cite this article

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.

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Acknowledgements

We would like to acknowledge our debt of gratitude to the efforts and results of the Collaborative Genetics of Alcoholism (COGA) consortium, and to the pioneering efforts to develop inbred alcohol preferring and non-preferring rat lines by T-K Li, L Lumeng and collaborators at Indiana University. This work was supported by funds from INGEN (Indiana Genomics Initiative at Indiana University) to ABN. This work was also supported by the Indiana Alcohol Research Center through P60AA007611 and the Integrative Neuroscience Initiative in Alcoholism through U01AA013518 (HJE, ZAR, WJM). Microarray data were generated in the Center for Medical Genomics at Indiana University School of Medicine, which is supported in part by INGEN (HJE). ABN would also like to thank Marc Schuckit for excellent clinical mentorship and introduction to the alcohol research field.

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Authors and Affiliations

  1. Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    Z A Rodd, B A Bertsch, W N Strother, H Le-Niculescu, Y Balaraman, E Hayden, J I Nurnberger Jr, W J McBride & A B Niculescu

  2. Department of Psychiatry, Laboratory of Neurophenomics, Indiana University School of Medicine, Indianapolis, IN, USA

    B A Bertsch, H Le-Niculescu, Y Balaraman & A B Niculescu

  3. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    R E Jerome & H J Edenberg

  4. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    L Lumeng

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  1. Z A Rodd
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The authors declare that they have no competing financial interests.

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website (http://www.nature.com/tpj)

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Rodd, Z., Bertsch, B., Strother, W. et al. Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach. Pharmacogenomics J 7, 222–256 (2007). https://doi.org/10.1038/sj.tpj.6500420

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  • DOI: https://doi.org/10.1038/sj.tpj.6500420

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