Ewens W J, Spielman R S
Department of Biology, University of Pennsylvania, Philadelphia 19104-6018, USA.
Am J Hum Genet. 1995 Aug;57(2):455-64.
Disease association with a genetic marker is often taken as a preliminary indication of linkage with disease susceptibility. However, population subdivision and admixture may lead to disease association even in the absence of linkage. In a previous paper, we described a test for linkage (and linkage disequilibrium) between a genetic marker and disease susceptibility; linkage is detected by this test only if association is also present. This transmission/disequilibrium test (TDT) is carried out with data on transmission of marker alleles from parents heterozygous for the marker to affected offspring. The TDT is a valid test for linkage and association, even when the association is caused by population subdivision and admixture. In the previous paper, we did not explicitly consider the effect of recent history on population structure. Here we extend the previous results by examining in detail the effects of subdivision and admixture, viewed as processes in population history. We describe two models for these processes. For both models, we analyze the properties of (a) the TDT as a test for linkage (and association) between marker and disease and (b) the conventional contingency statistic used with family data to test for population association. We show that the contingency test statistic does not have a chi 2 distribution if subdivision or admixture is present. In contrast, the TDT remains a valid chi 2 statistic for the linkage hypothesis, regardless of population history.
疾病与遗传标记之间的关联通常被视为与疾病易感性连锁的初步迹象。然而，群体细分和混合即使在没有连锁的情况下也可能导致疾病关联。在之前的一篇论文中，我们描述了一种检测遗传标记与疾病易感性之间连锁（以及连锁不平衡）的方法；只有当存在关联时，才能通过该方法检测到连锁。这种传递/不平衡检验（TDT）是利用标记等位基因从标记杂合的父母传递给患病后代的数据进行的。即使关联是由群体细分和混合引起的，TDT也是一种有效的连锁和关联检验方法。在之前的论文中，我们没有明确考虑近期历史对群体结构的影响。在这里，我们通过详细研究细分和混合的影响来扩展之前的结果，将其视为群体历史中的过程。我们描述了这两个过程的两种模型。对于这两种模型，我们分析了（a）作为标记与疾病之间连锁（和关联）检验的TDT的性质，以及（b）用于家庭数据以检验群体关联的传统列联统计量的性质。我们表明，如果存在细分或混合，列联检验统计量不具有卡方分布。相比之下，无论群体历史如何，TDT对于连锁假设仍然是一个有效的卡方统计量。
