Genetical genomic determinants of alcohol consumption in rats and humans
1 Department of Pharmacology, University of Colorado, Denver, Aurora, CO, USA
2 Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
3 Department of Pediatrics, University of California Irvine, Irvine, CA, USA
4 Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
5 Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
6 Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA
7 Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
8 Max Delbrück Center for Molecular Medicine, Berlin, Germany
9 Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
10 MRC Clinical Sciences Centre, London, UK
11 Department of Psychiatry, McGill University, Montreal, Quebec, Canada
12 Drug Health Services, Royal Prince Alfred Hospital, Sydney Medical School, University of Sydney, New South Wales, Australia
13 Queensland Institute of Medical Research, Queensland, Australia
14 School of Medicine, University of Queensland, Brisbane, Queensland, Australia
15 Division of Epidemiology, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA
16 Department Psychology-Neuroscience, University of Massachusetts Amherst, Amherst, MA, USA
17 Applied Biosystems, Lingley House, 120 Birchwood Blvd., Warrington, Cheshire, WA3 7QH, UK
BMC Biology 2009, 7:70 doi:10.1186/1741-7007-7-70Published: 27 October 2009
We have used a genetical genomic approach, in conjunction with phenotypic analysis of alcohol consumption, to identify candidate genes that predispose to varying levels of alcohol intake by HXB/BXH recombinant inbred rat strains. In addition, in two populations of humans, we assessed genetic polymorphisms associated with alcohol consumption using a custom genotyping array for 1,350 single nucleotide polymorphisms (SNPs). Our goal was to ascertain whether our approach, which relies on statistical and informatics techniques, and non-human animal models of alcohol drinking behavior, could inform interpretation of genetic association studies with human populations.
In the HXB/BXH recombinant inbred (RI) rats, correlation analysis of brain gene expression levels with alcohol consumption in a two-bottle choice paradigm, and filtering based on behavioral and gene expression quantitative trait locus (QTL) analyses, generated a list of candidate genes. A literature-based, functional analysis of the interactions of the products of these candidate genes defined pathways linked to presynaptic GABA release, activation of dopamine neurons, and postsynaptic GABA receptor trafficking, in brain regions including the hypothalamus, ventral tegmentum and amygdala. The analysis also implicated energy metabolism and caloric intake control as potential influences on alcohol consumption by the recombinant inbred rats. In the human populations, polymorphisms in genes associated with GABA synthesis and GABA receptors, as well as genes related to dopaminergic transmission, were associated with alcohol consumption.
Our results emphasize the importance of the signaling pathways identified using the non-human animal models, rather than single gene products, in identifying factors responsible for complex traits such as alcohol consumption. The results suggest cross-species similarities in pathways that influence predisposition to consume alcohol by rats and humans. The importance of a well-defined phenotype is also illustrated. Our results also suggest that different genetic factors predispose alcohol dependence versus the phenotype of alcohol consumption.