Candidate genes for alcohol preference identified by expression profiling in alcohol-preferring and -nonpreferring reciprocal congenic rats

Within the QTL region, 104 cis-regulated probe sets were differentially expressed in more than one region, and an additional 53 were differentially expressed in a single region. Fewer trans-regulated probe sets were detected, and most differed in only one region. Analysis of the average expression values across the 5 brain regions yielded 141 differentially expressed cis-regulated probe sets and 206 trans-regulated probe sets. Comparing the present results from inbred alcohol-preferring vs. congenic P.NP rats to earlier results from the reciprocal congenic NP.P vs. inbred alcohol-nonpreferring rats demonstrated that 74 cis-regulated probe sets were differentially expressed in the same direction and with a consistent magnitude of difference in at least one brain region.Cis-regulated candidate genes for alcohol consumption that lie within the chromosome 4 QTL were identified and confirmed by consistent results in two independent experiments with reciprocal congenic rats. These genes are strong candidates for affecting alcohol preference in the inbred alcohol-preferring and inbred alcohol-nonpreferring rats.Alcoholism has a substantial genetic component, with estimates of heritability ranging from 50 to 60% for both men and women [1-3]. The associations of several genes with risk for alcoholism have been replicated in human studies: GABRA2 [4-11], ADH4 [12-14], and CHRM2 [15,16]. Several other genes have been associated with alcoholism or related traits and await replication [17,18], including TAS2R16 [19,20], NTRK2 [21], GABRG3 [22], GABRA1 [23], OPRK1 and PDYN [24,25], NFKB1 [26], ANKK1 [27], ACN9 [28], TACR3 [29], CHRNA5 [30], SNCA [31], NPY [32,33], and NPY receptors [34].Selected strains of rodents that differ in voluntary alcohol consumption have been valuable tools to aid in dissecting the genetic components of alcoholism [35-38]. The alcohol-preferring (P) and -nonpreferring (NP) rat lines were developed through bi-directional selective breeding from a randomly