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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.

The mitochondrial ATP synthase, subunit c, isoform 3 gene (Atp5g3) encodes subunit 9, the subunit of the multisubunit enzyme that catalyzes ATP synthesis during oxidative phosphorylation in mitochondria. According to the Ensembl database, Atp5g3 in mice is located on chromosome 2 between 73746504 and 73749383 bp, within the genomic regions of two sets of quantitative trait loci - alcohol preference and body weight. Both of those traits are more influenced by epigenetic factors than many other traits are. Using currently available phenotype and gene expression profiles from the GeneNetwork database, we obtained correlations between Atp5g3 and alcoholism- and obesity-relevant phenotypes. The correlation in expression levels between Atp5g3 and each of its 12 partner genes in the molecular interaction are different in various tissues and genes. Transcriptome mapping indicated that Atp5g3 is differentially regulated in the hippocampus, cerebellum, and liver. Owing to a lack of known polymorphisms of Atp5g3 among three relevant mouse strains, C57BL/6J (B6), DBA/2J (D2), and BALB/ cJ, the molecular mechanism for the connection between Atp5g3 and alcoholism and body weight requires further investigation.