Xiong M, Fan R, Jin L
Human Genetics Center, University of Texas-Houston, Houston, Tex 77225, USA.
Hum Hered. 2002;53(3):158-72. doi: 10.1159/000064978.
As a dense map of single nucleotide polymorphism (SNP) markers are available, population-based linkage disequilibrium (LD) mapping or association study is becoming one of the major tools for identifying quantitative trait loci (QTL) and for fine gene mapping. However, in many cases, LD between the marker and trait locus is not very strong. Approaches that maximize the potential of detecting LD will be essential for the success of LD mapping of QTL. In this paper, we propose two strategies for increasing the probability of detecting LD: (1) phenotypic selection and (2) haplotype LD mapping. To provide the foundations for LD mapping of QTL under selection, we develop analytic tools for assessing the impact of phenotypic selection on allele and haplotype frequencies, and LD under three trait models: single trait locus, two unlinked trait loci, and two linked trait loci with or without epistasis. In addition to a traditional chi(2) test, which compares the difference in allele or haplotype frequencies in the selected sample and population sample, we present multiple regression methods for LD mapping of QTL, and investigate which methods are effective in employing phenotypic selection for QTL mapping. We also develop a statistical framework for investigating and comparing the power of the single marker and multilocus haplotype test for LD mapping of QTL. Finally, the proposed methods are applied to mapping QTL influencing variation in systolic blood pressure in an isolated Chinese population.
由于单核苷酸多态性(SNP)标记的密集图谱已经可用,基于群体的连锁不平衡(LD)作图或关联研究正成为识别数量性状基因座(QTL)和精细基因定位的主要工具之一。然而,在许多情况下,标记与性状基因座之间的LD并不是很强。最大化检测LD潜力的方法对于QTL的LD作图成功至关重要。在本文中,我们提出了两种提高检测LD概率的策略:(1)表型选择和(2)单倍型LD作图。为了为选择下的QTL的LD作图提供基础,我们开发了分析工具,用于评估表型选择对三种性状模型下的等位基因和单倍型频率以及LD的影响:单性状基因座、两个不连锁的性状基因座以及两个有或没有上位性的连锁性状基因座。除了传统的卡方检验(比较所选样本和群体样本中等位基因或单倍型频率的差异),我们还提出了用于QTL的LD作图的多元回归方法,并研究哪些方法在利用表型选择进行QTL作图时是有效的。我们还开发了一个统计框架,用于研究和比较单标记和多位点单倍型检验在QTL的LD作图中的功效。最后,将所提出的方法应用于定位影响一个隔离的中国人群收缩压变异的QTL。