Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
19874574
TITLE
Genetical genomic determinants of alcohol consumption in rats and humans.
ABSTRACT
BACKGROUND NlmCategory: 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 NlmCategory: 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 NlmCategory: 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.
DATE PUBLISHED
2009
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2009/09/29
accepted 2009/10/27
aheadofprint 2009/10/27
entrez 2009/10/31 06:00
pubmed 2009/10/31 06:00
medline 2010/01/16 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Tabakoff B Tabakoff Boris B Department of Pharmacology, University of Colorado, Denver, Aurora, CO, USA. boris.tabakoff@ucdenver.edu
Saba L Saba Laura L
Printz M Printz Morton M
Flodman P Flodman Pam P
Hodgkinson C Hodgkinson Colin C
Goldman D Goldman David D
Koob G Koob George G
Richardson HN Richardson Heather N HN
Kechris K Kechris Katerina K
Bell RL Bell Richard L RL
Hübner N Hübner Norbert N
Heinig M Heinig Matthias M
Pravenec M Pravenec Michal M
Mangion J Mangion Jonathan J
Legault L Legault Lucie L
Dongier M Dongier Maurice M
Conigrave KM Conigrave Katherine M KM
Whitfield JB Whitfield John B JB
Saunders J Saunders John J
Grant B Grant Bridget B
Hoffman PL Hoffman Paula L PL
WHO/ISBRA Study on State and Trait Markers of Alcoholism
INVESTIGATORS
JOURNAL
VOLUME: 7
ISSUE:
TITLE: BMC biology
ISOABBREVIATION: BMC Biol.
YEAR: 2009
MONTH:
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1741-7007
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: BMC Biol
COUNTRY: England
ISSNLINKING: 1741-7007
NLMUNIQUEID: 101190720
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
AA006420 NIAAA NIH HHS United States
AA013162 NIAAA NIH HHS United States
AA013517-INIA NIAAA NIH HHS United States
AA013522-INIA NIAAA NIH HHS United States
AA016649-INIA NIAAA NIH HHS United States
AA016663-INIA NIAAA NIH HHS United States
AA16922 NIAAA NIH HHS United States
HL35018 NHLBI NIH HHS United States
P60 AA006420 NIAAA NIH HHS United States
R24 AA013162 NIAAA NIH HHS United States
R24 AA015512 NIAAA NIH HHS United States
U01 AA013522 NIAAA NIH HHS United States
Howard Hughes Medical Institute United States
Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Alcohol Drinking metabolism
Animals metabolism
Brain metabolism
Brain Chemistry metabolism
Disease Models, Animal metabolism
Ethanol administration & dosage
Female administration & dosage
Food Preferences physiology
Gene Expression Profiling physiology
Genetic Predisposition to Disease physiology
Genomics physiology
Humans physiology
Male physiology
Microarray Analysis physiology
Phenotype physiology
Polymorphism, Single Nucleotide physiology
Quantitative Trait Loci physiology
Quantitative Trait, Heritable physiology
Rats physiology
Rats, Inbred Strains physiology
Species Specificity physiology
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
3K9958V90M Ethanol
OTHER ID's
OTHERID SOURCE
PMC2777866 NLM
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