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Chromosomal loci influencing chronic alcohol withdrawal severity

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Abstract

Ethanol (alcohol) withdrawal-induced convulsions are a key index of physical dependence on ethanol and a clinically important consequence of alcohol abuse in humans. In rodent models, severity of withdrawal is strongly influenced by genotype. For example, many studies have reported marked differences in withdrawal severity between the WSR (Withdrawal Seizure Resistant) and WSP (Withdrawal Seizure Prone) mouse strains selectively bred for over 25 generations to differ in chronic withdrawal severity. Therefore, we used an F2 intercross between the inbred WSP and WSR strains for a genome-wide search for quantitative trait loci (QTLs), which are chromosomal sites containing genes influencing the magnitude of withdrawal. We also used the recently developed HW, RHW (high withdrawal) and LW, RLW (low withdrawal) lines selectively bred for the same trait and in the same manner as the WSP, WSR lines. QTL analysis was then used to dissect the continuous trait distribution of withdrawal severity into component loci, and to map them to broad chromosomal regions by using the Pseudomarker 0.9 and Map Manager QT29b programs. This genome-wide search identified five significant QTLs influencing chronic withdrawal severity on Chromosomes (Chrs) 1 (proximal), 4 (mid), 8 (mid), 11 (proximal), and 14 (mid), plus significant interactions (epistasis) between loci on Chr 11 with 13, 4 with 8, and 8 with 14.

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Acknowledgements

Supported by AA10760 (Portland Alcohol Research Center), AA06243, DA05228, two VA Merit Review Programs (J.K. Belknap. J.C. Crabbe), two VA Senior Research Career Scientist Awards (J.K. Belknap, J.C. Crabbe), AA11463 to V.G. Erwin, and DA05925, AA013403, AA013182, and AA013475 awards to S.E. Bergeson. Appreciation is extended to Saunak Sen and Gary Churchill (The Jackson Laboratory) and Kenneth Manly (Roswell Park Institute) for making their excellent QTL computer programs available to the research community. We thank Catherine Merrill, Janet Dorow, Jason Schlumbohm, and Jason Sibert for excellent technical assistance.

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Authors and Affiliations

  1. Waggoner Center for Alcohol and Addiction Research, Section of Neurobiology, University of Texas, Austin, Texas 78712, USA

    Susan E. Bergeson & R. Kyle Warren

  2. Portland Alcohol Research Center, Research Service (R&D5), Veterans Affairs Medical Center, and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon 97201, USA

    John C. Crabbe, Pamela Metten & John K. Belknap

  3. School of Pharmacy (C238), University of Colorado Health Sciences Center, Denver, Colorado 80262, USA

    V. Gene Erwin

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  1. Susan E. Bergeson
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  2. R. Kyle Warren
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  3. John C. Crabbe
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  6. John K. Belknap
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Correspondence to John K. Belknap.

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Bergeson, S.E., Kyle Warren, R., Crabbe, J.C. et al. Chromosomal loci influencing chronic alcohol withdrawal severity . Mamm Genome 14, 454–463 (2003). https://doi.org/10.1007/s00335-002-2254-4

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