Koller Daniel L, Liu Lixiang, Alam Imranul, Sun Qiwei, Econs Michael J, Foroud Tatiana, Turner Charles H
Department of Medical and Molecular Genetics, Indiana University, Purdue University Indianapolis, Indianapolis, Indiana, USA.
J Bone Miner Res. 2008 Jan;23(1):41-7. doi: 10.1359/jbmr.071001.
To further delineate the factors underlying the complex genetic architecture of BMD in the rat model, a genome screen for epistatic interactions was conducted. Several significant interactions were identified, involving both previously identified and novel QTLs.
The variation in several of the risk factors for osteoporotic fracture, including BMD, has been shown to be caused largely by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We have previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 595 female F(2) progeny of Fischer 344 and Lewis rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk.
Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted BMD (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine a genome-wide significance threshold for the epistasis or interaction LOD score corresponding to an alpha level of 0.01.
Novel loci on chromosomes 12 and 15 showed a strong epistatic effect on total BMD at the femoral midshaft by pQCT (LOD = 5.4). A previously reported QTL on chromosome 7 was found to interact with a novel locus on chromosome 20 to affect whole lumbar BMD by pQCT (LOD = 6.2). These results provide new information regarding the mode of action of previously identified rat QTLs, as well as identifying novel loci that act in combination with known QTLs or with other novel loci to contribute to the risk factors for osteoporotic fracture.
为了进一步阐明大鼠模型中骨密度复杂遗传结构背后的因素，进行了全基因组上位性相互作用筛选。确定了几个显著的相互作用，涉及先前已鉴定的和新的数量性状基因座（QTL）。
骨质疏松性骨折的几个风险因素，包括骨密度的变异，已被证明很大程度上是由基因差异引起的。然而，骨密度的遗传结构在人类和模式生物中都很复杂。我们先前报道了对595只Fischer 344和Lewis大鼠的雌性F(2)后代进行全基因组筛选得到的骨密度数量性状基因座（QTL）结果。这些后代也为寻找对骨折风险有贡献的上位性效应或基因座间相互作用提供了绝佳机会。
使用R/qtl软件包分析了来自20厘摩全基因组筛选的微卫星标记数据以及体重调整后的骨密度（双能X线吸收法和外周定量CT）表型数据。对基因型和表型数据进行置换，以确定对应于0.01的α水平的上位性或相互作用LOD评分的全基因组显著性阈值。
12号和15号染色体上的新基因座对股骨中轴的总骨密度通过外周定量CT显示出强烈的上位性效应（LOD = 5.4）。发现先前报道的7号染色体上的一个QTL与20号染色体上的一个新基因座相互作用，通过外周定量CT影响整个腰椎骨密度（LOD = 6.2）。这些结果提供了关于先前鉴定的大鼠QTL作用模式的新信息，同时也鉴定出了与已知QTL或其他新基因座联合作用以促成骨质疏松性骨折风险因素的新基因座。
