Genetical genomic determinants of alcohol consumption in rats and humans

Abstract

Background: 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.

Results: 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.

Conclusion: 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.

Figure 1

Strain Distribution of Average Daily Ethanol Consumption. Rats were given 10% ethanol as their only choice of fluid for one week (week 0). For the next seven weeks, rats were given a choice of two bottles, one with water and one with a 10% ethanol solution. The data shown are mean ± SEM of average daily ethanol consumption (g/kg body weight) during the second week of the two-bottle choice paradigm.

Figure 2

QTLs for Alcohol Consumption by HXB/BXH RI Rat Strains. Behavioral QTLs (bQTLs) were calculated using the data shown in Figure 1. Individual values were not included if they were more than two standard deviations from the strain mean. The STAR Consortium SNP markers (The STAR Consortium, 2008) were used for this analysis. There were 21 RI strains and the two progenitor strains that had both alcohol consumption and SNP data. Strain means for alcohol consumption were used in a marker regression QTL analysis, which was conducted using the R/qtl package in R. The 20 Mb region around the suggestive markers was used as the bQTL interval shown.

Figure 3

Candidate Genes from HXB/BXH RI Rat Strain Microarray Analysis Proposed for Presynaptic GABA Neuron Terminal and Postsynaptic Neuron. The identified candidate genes are indicated by rectangles. Presynaptic gene products are suggested to modulate GABA release, and postsynaptic gene products affect GABA_A receptor localization and trafficking in VTA dopaminergic neurons.