Genetical genomic determinants of alcohol consumption in rats and humans.
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.


CONCLUSIONS
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.
Tabakoff
Boris
B
Department of Pharmacology, University of Colorado, Denver, Aurora, CO, USA. boris.tabakoff@ucdenver.edu
Saba
Laura
L
Printz
Morton
M
Flodman
Pam
P
Hodgkinson
Colin
C
Goldman
David
D
Koob
George
G
Richardson
Heather N
HN
Kechris
Katerina
K
Bell
Richard L
RL
Hübner
Norbert
N
Heinig
Matthias
M
Pravenec
Michal
M
Mangion
Jonathan
J
Legault
Lucie
L
Dongier
Maurice
M
Conigrave
Katherine M
KM
Whitfield
John B
JB
Saunders
John
J
Grant
Bridget
B
Hoffman
Paula L
PL
D000428:Alcohol Drinking / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D005518:Food Preferences / Q000502:physiology*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D000431:Ethanol