Solberg Leah C, Baum Amber E, Ahmadiyeh Nasim, Shimomura Kazuhiro, Li Renhua, Turek Fred W, Churchill Gary A, Takahashi Joseph S, Redei Eva E
Department of Psychiatry and Behavioral Science, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, Illinois 60611, USA.
Mamm Genome. 2004 Aug;15(8):648-62. doi: 10.1007/s00335-004-2326-z.
The Wistar-Kyoto (WKY) rat exhibits physiological and behavioral similarities to endophenotypes of human depression. In the forced swim test (FST), a well-characterized antidepressant-reversible test for behavioral despair in rodents, WKYs express characteristics of behavioral despair; increased immobility, and decreased climbing. To map genetic loci linked to behavior in the FST, we conducted a quantitative trait loci (QTL) analysis of the segregating F2 generation of a WKY x Fisher 344 (F344) reciprocal intercross. Using linear-model-based genome scans to include covariate (sex or lineage)-by-QTL interaction effects, four significant QTL influencing climbing behavior were identified. In addition, we identified three, seven, and two suggestive QTL for climbing, immobility, and swimming, respectively. One of these loci was pleiotropic, affecting both immobility and climbing. As found in human linkage studies, several of these QTL showed sex- and/or lineage-dependent effects. A simultaneous search strategy identified three epistatic locus pairs for climbing. Multiple regression analysis was employed to characterize the joint contributions of these QTL and to clarify the sex- and lineage-dependent effects. As expected for complex traits, FST behavior is influenced by multiple QTL of small effect, each contributing 5%-10%, accounting for a total 10%-30% of the phenotypic variance. A number of loci mapped in this study share overlapping candidate regions with previously identified emotionality QTL in mice as well as with susceptibility loci recognized by linkage or genome scan analyses for major depression or bipolar disorder in humans. The presence of these loci across species suggests that these QTL may represent universal genetic factors contributing to mood disorders.
Wistar-Kyoto(WKY)大鼠在生理和行为上与人类抑郁症的内表型相似。在强迫游泳试验(FST)中,这是一种针对啮齿动物行为绝望的特征明确的抗抑郁药可逆试验,WKY大鼠表现出行为绝望的特征;不动时间增加,攀爬减少。为了绘制与FST行为相关的基因座,我们对WKY与Fisher 344(F344)相互杂交的分离F2代进行了数量性状基因座(QTL)分析。使用基于线性模型的基因组扫描来纳入协变量(性别或品系)与QTL的相互作用效应,确定了四个影响攀爬行为的显著QTL。此外,我们分别确定了三个、七个和两个暗示性的攀爬、不动和游泳QTL。其中一个基因座具有多效性,影响不动和攀爬。正如在人类连锁研究中发现的那样,这些QTL中有几个表现出性别和/或品系依赖性效应。同时搜索策略确定了三个攀爬的上位性基因座对。采用多元回归分析来表征这些QTL的联合贡献,并阐明性别和品系依赖性效应。正如对复杂性状所预期的那样,FST行为受多个小效应QTL的影响,每个QTL贡献5%-10%,占表型变异的10%-30%。本研究中定位的许多基因座与先前在小鼠中鉴定的情绪性QTL以及人类主要抑郁症或双相情感障碍的连锁或基因组扫描分析所识别的易感基因座共享重叠的候选区域。这些基因座在不同物种中的存在表明,这些QTL可能代表导致情绪障碍的普遍遗传因素。