Genetic Dissection of Quantitative Trait Loci Specifying Sedative/Hypnotic Sensitivity to Ethanol: Mapping With Interval-Specific Congenic Recombinant Lines

Bennett, Beth; Beeson, Mary; Gordon, Lena; Carosone-Link, Phyllis; Johnson, Thomas E.

doi:10.1097/00000374-200211000-00003

Cited by 23 publications

(57 citation statements)

References 28 publications

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“…The latter cross confirmed four of the putative QTLs from the LSXSS and identified three novel regions. We confirmed and captured four of the major QTLs for this trait, on chromosomes 1, 2, 11, and 15, in reciprocal congenic strains (Bennett et al, 2002b), and we narrowed the interval surrounding the QTL on two chromosomes to less than 12 megabases (Mb) (Bennett et al, 2002a).…”

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confidence: 73%

“…Both F 2 mapping (Markel et al, 1997) and interval-specific congenic recombinant strain (ISCR) confirmation (Bennett et al, 2002a) identified a slightly more proximal region on chr 1 than did the LXS. Of six ISCR, four carried a proximal region of ILS on an ISS background, whereas two carried the more telomeric ILS region, identified in the LXS.…”

Section: Discussionmentioning

confidence: 99%

“…2. The chr 15 region shows a more complicated picture, which could be due to a similar phenomenon producing a GXE interaction (LOD ϭ 2.2); break up of the QTL into multiple, linked QTLs (as suggested by analysis of interval-specific congenic strains; Bennett et al, 2002a); or a combination of these factors.…”

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confidence: 99%

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Confirmation and Fine Mapping of Ethanol Sensitivity Quantitative Trait Loci, and Candidate Gene Testing in the LXS Recombinant Inbred Mice

Bennett

Carosone-Link²,

Zahniser³

et al. 2006

J Pharmacol Exp Ther

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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.

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confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Confirmation and Fine Mapping of Ethanol Sensitivity Quantitative Trait Loci, and Candidate Gene Testing in the LXS Recombinant Inbred Mice

Bennett

Carosone-Link²,

Zahniser³

et al. 2006

J Pharmacol Exp Ther

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“…Among these are regions on chromosomes 11 and 15, where the loci for AC1 and AC8 are located, respectively. The QTL for ethanolinduced sedation on chromosome 11 has been efficiently recombined away from the locus for AC1 during generation of lines (see Materials and Methods for details) and cannot contribute to the effects we described here (Bennett et al, 2002). In contrast, a QTL for ethanol consumption on chromosome 15 is linked to our 129/Sv-derived locus for AC8, and it is possible that the altered ethanol consumption in AC8 KO mice may be associated with the presence of a different gene associated with this QTL (Vadasz et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Calcium-Stimulated Adenylyl Cyclases Are Critical Modulators of Neuronal Ethanol Sensitivity

et al. 2005

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The importance of the cAMP signaling pathway in the modulation of ethanol sensitivity has been suggested by studies in organisms from Drosophila melanogaster to man. However, the involvement of specific isoforms of adenylyl cyclase (AC), the molecule that converts ATP to cAMP, has not been systemically determined in vivo. Because AC1 and AC8 are the only AC isoforms stimulated by calcium, and ethanol modulates calcium flux by the NMDA receptor, we hypothesized that these ACs would be important in the neural response to ethanol. AC1 knock-out (KO) mice and double knock-out (DKO) mice with genetic deletion of both AC1 and AC8 display substantially increased sensitivity to ethanol-induced sedation compared with wild-type (WT) mice, whereas AC8 KO mice are only minimally more sensitive. In contrast, AC8 KO and DKO mice, but not AC1 KO mice, demonstrate decreased voluntary ethanol consumption compared with WT mice. DKO mice do not display increased sleep time compared with WT mice after administration of ketamine or pentobarbital, indicating that the mechanism of enhanced ethanol sensitivity in these mice is likely distinct from the antagonism of ethanol of the NMDA receptor and potentiation of the GABA A receptor. Ethanol does not enhance calcium-stimulated AC activity, but the ethanol-induced phosphorylation of a discrete subset of protein kinase A (PKA) substrates is compromised in the brains of DKO mice. These results indicate that the unique activation of PKA signaling mediated by the calcium-stimulated ACs is an important component of the neuronal response to ethanol.

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“…QTL intervals were mapped in inbred lines 31,32 and coding differences between lines were identified in eight genes in the QTL intervals. Mapping in interval-specific congenic recombinant mice, 33 which carry smaller, overlapping sections of the QTL intervals, showed that only the observed coding sequence changes in Zfp142 or Ptprn in one interval, and Zfp133 in another, could account for the phenotypic difference. 34 An expression-array study of multiple trait-selected and isogenic mouse lines found that the target binding sequence for Zfp143 was over-represented in the promoter regions of genes showing increased expression in high ethanol-consuming lines, and that expression of Zfp143, a known transcriptional activator, 35 was also increased in these lines.…”

Section: Discussionmentioning

confidence: 99%

Alcohol dependence is associated with the ZNF699 gene, a human locus related to Drosophila hangover, in the Irish affected sib pair study of alcohol dependence (IASPSAD) sample

et al. 2006

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Because tolerance is an important aspect of alcohol dependence (AD) in humans, recent evidence showing that the Drosophila gene hang is critically involved in the development of alcohol tolerance in the fly suggests that variation in related human loci might be important in the etiology of alcohol-related disorders. The orthology of hang in mammals is complex, but a number of human gene products (including ZNF699) with similar levels of amino-acid identity (18-26%) and similarity (30-41%), are consistently identified as the best matches with the translated hang sequence. We tested for association between the dichotomous clinical phenotype of alcohol dependence and seven single nucleotide polymorphisms (SNPs) in ZNF699 in our sample of 565 genetically independent cases and 496 siblings diagnosed with AD, and 609 controls. In analyses of genetically independent cases and controls, four of the seven single markers show strong evidence for association with AD (0.00003 < Fisher's exact P < 0.001), and the most significant single marker, rs7254880, tags an associated haplotype with frequency 0.071 in cases compared to 0.034 in controls (v 2 15.563, P < 0.00008, 5000 permutation P < 0.001, OR 2.17); inclusion of affected siblings gives similar results. Expression analyses conducted in independent postmortem brain samples show that expression of ZNF699 mRNA is significantly reduced in the dorsolateral prefrontal cortex of individuals carrying this haplotype compared with other observed haplotype combinations.

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Genetic Dissection of Quantitative Trait Loci Specifying Sedative/Hypnotic Sensitivity to Ethanol: Mapping With Interval-Specific Congenic Recombinant Lines

Abstract: Use of ISCR lines can narrow each Lore candidate region to a few centimorgans. Such an interval size is conducive to brute-force approaches to identify candidate genes, entailing bioinformatics, gene expression, and DNA sequencing strategies.

Cited by 23 publications

References 28 publications

Confirmation and Fine Mapping of Ethanol Sensitivity Quantitative Trait Loci, and Candidate Gene Testing in the LXS Recombinant Inbred Mice

Confirmation and Fine Mapping of Ethanol Sensitivity Quantitative Trait Loci, and Candidate Gene Testing in the LXS Recombinant Inbred Mice

Calcium-Stimulated Adenylyl Cyclases Are Critical Modulators of Neuronal Ethanol Sensitivity

Alcohol dependence is associated with the ZNF699 gene, a human locus related to Drosophila hangover, in the Irish affected sib pair study of alcohol dependence (IASPSAD) sample

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