Genetical genomic determinants of alcohol consumption in rats and humans
Copyright policy )Genetical genomic determinants of alcohol consumption in rats and humans
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.
- DePaul University United States
- McGill University Canada
- University of Sydney Australia
- University of Queensland Australia
- University of Colorado System United States
Male, 1105 Ecology, hippocampal dentate gyrus, 1307 Cell Biology, 1309 Developmental Biology, 1100 Agricultural and Biological Sciences, 1315 Structural Biology, Food intake, 1110 Plant Science, Psychology, Biology (General), Agricultural and Biological Sciences(all), ethanol intake, Brain, food-intake, Genomics, Phenotype, 1305 Biotechnology, Female, candidate genes, 1300 Biochemistry, Alcohol Drinking, Evolution, QH301-705.5, Quantitative Trait Loci, ventral tegmental area, Genetics and Molecular Biology, Polymorphism, Single Nucleotide, Food Preferences, Quantitative Trait, Heritable, Behavior and Systematics, nucleus-accumbens, 616, Animals, Humans, Genetic Predisposition to Disease, Brain Chemistry, melanocortin-4 receptor, Ethanol, Protease-activated receptors, Biochemistry, Genetics and Molecular Biology(all), Gene Expression Profiling, protease-activated receptors, gabaergic transmission, Rats, Inbred Strains, 1314 Physiology, Microarray Analysis, Rats, Disease Models, Animal, Central nervous system, central-nervous-system, Ventral tegmental area
Male, 1105 Ecology, hippocampal dentate gyrus, 1307 Cell Biology, 1309 Developmental Biology, 1100 Agricultural and Biological Sciences, 1315 Structural Biology, Food intake, 1110 Plant Science, Psychology, Biology (General), Agricultural and Biological Sciences(all), ethanol intake, Brain, food-intake, Genomics, Phenotype, 1305 Biotechnology, Female, candidate genes, 1300 Biochemistry, Alcohol Drinking, Evolution, QH301-705.5, Quantitative Trait Loci, ventral tegmental area, Genetics and Molecular Biology, Polymorphism, Single Nucleotide, Food Preferences, Quantitative Trait, Heritable, Behavior and Systematics, nucleus-accumbens, 616, Animals, Humans, Genetic Predisposition to Disease, Brain Chemistry, melanocortin-4 receptor, Ethanol, Protease-activated receptors, Biochemistry, Genetics and Molecular Biology(all), Gene Expression Profiling, protease-activated receptors, gabaergic transmission, Rats, Inbred Strains, 1314 Physiology, Microarray Analysis, Rats, Disease Models, Animal, Central nervous system, central-nervous-system, Ventral tegmental area
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