Received for publication March 6, 2006.
Revised June 23, 2006.
Accepted for publication June 26, 2006.

Confirmation and Fine Mapping of Ethanol Sensitivity QTLs, 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 F₂ 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 (ILS) and Inbred Short Sleep (ISS) strains. We expected to improve mapping resolution in the QTL regions and to identify novel QTLs for loss of the righting reflex following ethanol (LORE). We used three common mapping algorithms (R/qtl, QTL Cartographer, and WebQTL) to map QTLs in the LXS, and compared the results. Most mapping studies use only a single algorithm, an approach which 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 over 4000 polymorphic SNP 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 utilizing these RI strains to assess evidence for candidate genes in the narrowed intervals, and apply this method to a strong candidate, the serotonin transporter.

Key words: Candidate Gene Testing, Ethanol sensitivity, LXS RI Panel, QTL Mapping, Recombinant Inbreds, Serotonin Transporter