title: Critical evaluation of transcription factor Atf2 as a candidate modulator of alcohol preference in mouse and human populations.
abstract: In prior work, congenic strains carrying the DBA/2Igb (D2) region of chromosome 2 (Chr2) for alcohol preference were bred onto a C57BL/6Ibg (B6) background and as predicted were found to reduce voluntary consumption. Subsequently, interval-specific congenic recombinant strains (ISCRS) were generated and also tested. These ISCRS strains reduced the quantitative trait loci (QTL) interval to a comparatively small 3.4 Mb region. Here, we have exploited an integrative approach using both murine and human populations to critically evaluate candidate genes within this region. First, we used bioinformatics tools to search for genes relevant to alcohol preference within the QTL region. Second, we searched for single nucleotide polymorphisms (SNPs) within exons of every gene in this region. Third, we conducted follow-up microarray analyses to identify differentially expressed genes between the B6 and ISCRS strains in mice from each group. Fourth, we analyzed correlations between the expression level of candidate genes and phenotypes of alcohol preference in a large family of BXD recombinant inbred strains derived from B6 and D2. Finally, we evaluated SNP segregation in both BXD mouse strains and in humans who were heavy alcohol drinkers or non-drinkers. Among several potential candidate genes in this region, we identified activating transcription factor 2 (Atf2) as the most plausible gene that would influence alcohol preference. However, the candidacy of Atf2 was only weakly supported when we used a genetic network approach and by focused reanalysis of genome-wide association study data from European-American and African-American populations. Thus, we cannot conclude that Atf2 plays a role in the regulation of the QTL of mouse Chr2.
authors: Department of Orthopaedic Surgery and BioMedical Engineering, Campbell Clinic, University of Tennessee Health Science Center, Memphis, TN, USA.
authors: L S
authors: LS
authors: Wang
authors: Y
authors: Y
authors: Jiao
authors: Y
authors: Y
authors: Huang
authors: X Y
authors: XY
authors: Liu
authors: G
authors: G
authors: Gibson
authors: B
authors: B
authors: Bennett
authors: K M
authors: KM
authors: Hamre
authors: D W
authors: DW
authors: Li
authors: H Y
authors: HY
authors: Zhao
authors: J
authors: J
authors: Gelernter
authors: H R
authors: HR
authors: Kranzler
authors: L A
authors: LA
authors: Farrer
authors: L
authors: L
authors: Lu
authors: Y J
authors: YJ
authors: Wang
authors: W K
authors: WK
authors: Gu
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics* / Q000378:metabolism; D000428:Alcohol Drinking / Q000235:genetics*; D000437:Alcoholism / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002889:Chromosomes, Human, Pair 2; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA; D059467:Transcriptome
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2