Ignoring linkage disequilibrium among tightly linked markers induces false-positive evidence of linkage for affected sib pair analysis
Ignoring linkage disequilibrium among tightly linked markers induces false-positive evidence of linkage for affected sib pair analysis
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DOI：
10.1086/426000
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发表时间：
2004-12-01
影响因子：
9.8
通讯作者：
Amos, CI
中科院分区：
文献类型：
--
作者：
Huang, QQ;Shete, S;Amos, CI
大多数多点连锁程序都假定所研究的标记之间存在连锁平衡。这一假设适用于标记间距离超过几厘摩的稀疏标记的研究，因为几乎所有的群体在这些间隔上都有望达到连锁平衡。然而，随着近年来高通量基因分型技术的发展，可获得更密集的标记，并且标记之间可能存在连锁不平衡（LD）。将假定连锁平衡的连锁分析应用于密集标记可能导致偏倚。在这里，我们证明，当一些或所有的父母基因型缺失，假设紧密连锁的标记之间的连锁平衡，强LD存在可能会导致明显的过度共享多点身份下降（IBD）之间的同胞对和假阳性证据的多点无模型连锁分析受影响的同胞对数据。LD还可以模拟疾病位点和多个紧密连锁的标记之间的连锁，从而使用参数模型导致连锁的假阳性证据，特别是当应用异质性LOD评分方法时。偏差可以通过纳入父母基因型数据来消除，并且当分析中纳入其他未受影响的兄弟姐妹时可以减少偏差。
Most multipoint linkage programs assume linkage equilibrium among the markers being studied. The assumption is appropriate for the study of sparsely spaced markers with intermarker distances exceeding a few centimorgans, because linkage equilibrium is expected over these intervals for almost all populations. However, with recent advancements in high-throughput genotyping technology, much denser markers are available, and linkage disequilibrium (LD) may exist among the markers. Applying linkage analyses that assume linkage equilibrium to dense markers may lead to bias. Here, we demonstrated that, when some or all of the parental genotypes are missing, assuming linkage equilibrium among tightly linked markers where strong LD exists can cause apparent oversharing of multipoint identity by descent (IBD) between sib pairs and false-positive evidence for multipoint model-free linkage analysis of affected sib pair data. LD can also mimic linkage between a disease locus and multiple tightly linked markers, thus causing false-positive evidence of linkage using parametric models, particularly when heterogeneity LOD score approaches are applied. Bias can be eliminated by inclusion of parental genotype data and can be reduced when additional unaffected siblings are included in the analysis.