Confirmation and fine mapping of ethanol sensitivity quantitative trait loci, and candidate gene testing in the LXS recombinant inbred mice

Abstract

In previous studies, we have mapped quantitative trait loci (QTLs) for hypnotic sensitivity to ethanol using a small recombinant inbred (RI) panel and a large F(2) backcross. Alcohol sensitivity is a major predictor of long-term risk for alcoholism. We remapped hypnotic sensitivity using a new set of 75 RI strains, the LXS, derived from Inbred Long Sleep and Inbred Short Sleep strains. We expected to improve mapping resolution in the QTL regions and to identify novel QTLs for loss of the righting reflex due to ethanol. We used three common mapping algorithms (R/qtl, QTL Cartographer, and WebQTL) to map QTLs in the LXS, and we compared the results. Most mapping studies use only a single algorithm, an approach that may result in failure to identify minor QTLs. We confirmed most of our previously reported QTLs, although one major QTL from earlier work (Lore2) failed to replicate, possibly because it represented multiple linked genes separated by recombination in the RI strains. We also report narrowed confidence intervals, based on mapping with a new genetic resource of more than 4000 polymorphic single-nucleotide polymorphism markers. These narrowed confidence intervals will facilitate candidate gene identification and assessment of overlap with human regions specifying risk for alcoholism. Finally, we present an approach for using these RI strains to assess evidence for candidate genes in the narrowed intervals, and we apply this method to a strong candidate, the serotonin transporter.