Bergeson Susan E, Kyle Warren R, Crabbe John C, Metten Pamela, Gene Erwin V, Belknap John K
Waggoner Center for Alcohol and Addiction Research, Section of Neurobiology, University of Texas, Austin, Texas 78712, USA.
Mamm Genome. 2003 Jul;14(7):454-63. doi: 10.1007/s00335-002-2254-4.
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 F(2) 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.
乙醇（酒精）戒断所致惊厥是对乙醇身体依赖的关键指标，也是人类酒精滥用的一个重要临床后果。在啮齿动物模型中，戒断的严重程度受基因型的强烈影响。例如，许多研究报告称，经过超过25代选择性培育以在慢性戒断严重程度上存在差异的WSR（戒断惊厥抗性）和WSP（戒断惊厥易感）小鼠品系之间，戒断严重程度存在显著差异。因此，我们利用近交WSP和WSR品系之间的F(2)杂交进行全基因组搜索，以寻找数量性状基因座（QTL），即包含影响戒断程度的基因的染色体位点。我们还使用了最近开发的HW、RHW（高戒断）和LW、RLW（低戒断）品系，它们是针对与WSP、WSR品系相同的性状并以相同方式选择性培育的。然后使用QTL分析将戒断严重程度的连续性状分布分解为组成基因座，并通过使用伪标记0.9和Map Manager QT29b程序将它们定位到广泛的染色体区域。这项全基因组搜索在染色体（Chrs）1（近端）、4（中部）、8（中部）、11（近端）和14（中部）上鉴定出五个影响慢性戒断严重程度的显著QTL，以及11号染色体上的基因座与13号染色体、4号染色体与8号染色体、8号染色体与14号染色体之间的显著相互作用（上位性）。
