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 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.
Footnotes
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This work was supported by National Institutes of Health Grants R01 AA11984 and AA008940 (to T.E.J.) and AA014666 and DA015663 (supporting the SPF), the Ellison Foundation for Medical Research (to T.E.J.), and by funds from the University of Colorado Denver Health Sciences Center (5 K05 DA015050-04) (to N.R.Z.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.103572.
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ABBREVIATIONS: ILS, Inbred Long Sleep; ISS, Inbred Short Sleep; QTL, quantitative trait loci; LORE, loss of the righting reflex due to ethanol; Lore, QTL for LORE; RI, recombinant inbred; LS, Long Sleep; SS, Short Sleep; LXS, RI panel derived from ILS × ISS cross; GXE, gene-environment; NET, norepinephrine transporter; chr, chromosome; SERT, serotonin transporter; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); SPF, specific pathogen-free; BEC, blood ethanol concentration; SNP, single-nucleotide polymorphism; kb, kilobase; LOD, logarithm of the odds; Xrcc5, X-ray repair complementing defective repair in Chinese hamster cells; ISCR, interval-specific congenic recombinant; NE, norepinephrine.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received February 27, 2006.
- Accepted June 26, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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