title: Identification of candidate genes that underlie the QTL on chromosome 1 that mediates genetic differences in stress-ethanol interactions.
abstract: Alcoholism, stress, and anxiety are strongly interacting heritable, polygenetic traits. In a previous study, we identified a quantitative trait locus (QTL) on murine chromosome (Chr) 1 between 23.0 and 31.5 Mb that modulates genetic differences in the effects of ethanol on anxiety-related phenotypes. The goal of the present study was to extend the analysis of this locus with a focus on identifying candidate genes using newly available data and tools. Anxiety-like behavior was evaluated with an elevated zero maze following saline or ethanol injections (1.8 g/kg) in C57BL/6J, DBA2J, and 72 BXD strains. We detected significant effects of strain and treatment and their interaction on anxiety-related behaviors, although surprisingly, sex was not a significant factor. The Chr1 QTL is specific to the ethanol-treated cohort. Candidate genes in this locus were evaluated using now standard bioinformatic criteria. Collagen 19a1 (Col19a1) and family sequence 135a (Fam135a) met most criteria but have lower expression levels and lacked biological verification and, therefore, were considered less likely candidates. In contrast, two other genes, the prenylated protein tyrosine phosphate family member Ptp4a1 (protein tyrosine phosphate 4a1) and the zinc finger protein Phf3 (plant homeoDomain finger protein 3) met each of our bioinformatic criteria and are thus strong candidates. These findings are also of translational relevance because both Ptp4a1 and Phf3 have been nominated as candidates genes for alcohol dependence in a human genome-wide association study. Our findings support the hypothesis that variants in one or both of these genes modulate heritable differences in the effects of ethanol on anxiety-related behaviors.
authors.affiliation: Department of Psychology, University of Memphis, Memphis, Tennessee;
authors.forename: Melloni N
authors.initials: MN
authors.lastname: Cook
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee; Department of Neuroscience, Rhodes College, Memphis, Tennessee.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Baker
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee;
authors.forename: Scott A
authors.initials: SA
authors.lastname: Heldt
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee;
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee;
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Hamre
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee; Jiangsu Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, China; and lulu@uthsc.edu.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D033481:Chromosomes, Mammalian / Q000235:genetics*; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D056726:Genetic Association Studies; D017874:Immediate-Early Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D010641:Phenotype; D011110:Polymorphism, Genetic; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: D017874:Immediate-Early Proteins; D000431:Ethanol; D017027:Protein Tyrosine Phosphatases; C087359:Ptp4a1 protein, mouse
keywords: BXD mice; gene expression; quantitative trait locus (QTL), elevated zero maze