Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis

doi:10.1073/pnas.0510188103

Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis

*Waggoner Center for Alcohol and Addiction Research and
Sections of ^†Neurobiology and
**Molecular Genetics and Microbiology, University of Texas, Austin, TX 78712;
^§Department of Veterans Affairs Medical Center, Portland Alcohol Research Center, and Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239;
^¶University of Colorado Health Sciences Center, Aurora, CO 80045;
^‖Indiana University School of Medicine, Indianapolis, IN 46202; and
^††The Scripps Research Institute, La Jolla, CA 92037

Edited by Floyd E. Bloom, The Scripps Research Institute, La Jolla, CA, and approved February 9, 2006
↵ ^‡M.K.M. and I.P. contributed equally to this work. (received for review November 30, 2005)

Abstract

Much evidence from studies in humans and animals supports the hypothesis that alcohol addiction is a complex disease with both hereditary and environmental influences. Molecular determinants of excessive alcohol consumption are difficult to study in humans. However, several rodent models show a high or low degree of alcohol preference, which provides a unique opportunity to approach the molecular complexities underlying the genetic predisposition to drink alcohol. Microarray analyses of brain gene expression in three selected lines, and six isogenic strains of mice known to differ markedly in voluntary alcohol consumption provided >4.5 million data points for a meta-analysis. A total of 107 arrays were obtained and arranged into six experimental data sets, allowing the identification of 3,800 unique genes significantly and consistently changed between all models of high or low amounts of alcohol consumption. Several functional groups, including mitogen-activated protein kinase signaling and transcription regulation pathways, were found to be significantly overrepresented and may play an important role in establishing a high level of voluntary alcohol drinking in these mouse models. Data from the general meta-analysis was further filtered by a congenic strain microarray set, from which cis-regulated candidate genes for an alcohol preference quantitative trait locus on chromosome 9 were identified: Arhgef12, Carm1, Cryab, Cox5a, Dlat, Fxyd6, Limd1, Nicn1, Nmnat3, Pknox2, Rbp1, Sc5d, Scn4b, Tcf12, Vps11, and Zfp291 and four ESTs. The present study demonstrates the use of (i) a microarray meta-analysis to analyze a behavioral phenotype (in this case, alcohol preference) and (ii) a congenic strain for identification of cis regulation.

Footnotes

^‡‡To whom correspondence should be addressed at:
Waggoner Center for Alcohol and Addiction Research and Section of Neurobiology, University of Texas, A4800, MBB1.138AA, 1 University Station, Austin, TX 78712.
E-mail: bergeson{at}mail.utexas.edu
Author contributions: M.K.M., I.P., R.J.H., J.K.B., R.A.H., Y.A.B., G.F.K., and S.E.B. designed research; M.K.M., R.J.H., J.K.B., B.T., J.C.C., N.J.G., T.J.P., D.A.F., P.L.H., and S.E.B. performed research; R.J.H., J.K.B., J.C.C., N.J.G., and T.J.P. contributed new reagents/analytic tools; M.K.M., I.P., R.J.H., J.K.B., B.T., Y.A.B., P.L.H., and S.E.B. analyzed data; and M.K.M., I.P., J.K.B., R.A.H., Y.A.B., V.R.I., G.F.K., and S.E.B. wrote the paper.
↵ ^§§Behm, A. L. L., Li, T. K. & Grahame, N. (2003) Alcohol. Clin. Exp. Res. 27, 49A, abstr.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

B6,

C57BL/6J;

D2,

DBA/2J;

QTG,

quantitative trait gene;

QTL,

quantitative trait locus;

TF,

transcription factor;

TFBS,

TF binding site(s).