Greenberg D A, Doneshka P
Department of Psychiatry, Mount Sinai Medical Center, New York, New York 10029, USA.
Genet Epidemiol. 1996;13(3):243-52. doi: 10.1002/(SICI)1098-2272(1996)13:3<243::AID-GEPI2>3.0.CO;2-7.
Marker allele-disease association and linkage between a disease locus and a marker locus are two different phenomena. Linkage without evidence of association and association without evidence of linkage are possible observations. Linkage analysis uses marker loci and the phenomenon of recombination to look for disease-related loci which are presumably major contributors to disease expression ("necessary" loci). However, the phenomenon of association is more complex. One explanation for the existence of an association is that there is a "necessary" locus in linkage disequilibrium with a marker locus. Another explanation is that the marker locus itself (or a closely linked locus in linkage disequilibrium with the marker) is a "susceptibility" locus, which increases the probability of contracting the disease but is not necessary for disease expression. Although there are other possible explanations for the existence of an association, these two can lead to different results when family data from a disease showing association are analyzed for linkage between the associated marker and the disease. If the linkage disequilibrium hypothesis is correct, there will be evidence for linkage. If the susceptibility locus hypothesis is correct, there may be strong evidence against linkage. In this work, we explore a method that could indicate whether an association is due to a susceptibility locus or a necessary locus. We show that, by dividing families based on the presence or absence of the associated marker allele in a randomly chosen affected sib, calculating lod scores, and then calculating a heterogeneity statistic, we could distinguish whether linkage data came from a susceptibility locus or a necessary locus.
标记等位基因与疾病的关联以及疾病位点与标记位点之间的连锁是两种不同的现象。存在无关联证据的连锁以及无连锁证据的关联都是可能观察到的情况。连锁分析利用标记位点和重组现象来寻找可能是疾病表现主要贡献者的疾病相关位点（“必需”位点）。然而，关联现象更为复杂。对于关联存在的一种解释是，存在一个与标记位点处于连锁不平衡状态的“必需”位点。另一种解释是，标记位点本身（或与该标记处于连锁不平衡状态的紧密连锁位点）是一个“易感”位点，它增加了患该疾病的概率，但对于疾病表现并非必需。尽管对于关联的存在还有其他可能的解释，但当对显示关联的疾病的家系数据进行关联标记与疾病之间的连锁分析时，这两种解释会导致不同的结果。如果连锁不平衡假说是正确的，将会有连锁的证据。如果易感位点假说是正确的，可能会有强烈的反对连锁的证据。在这项工作中，我们探索了一种方法，该方法可以表明一种关联是由于易感位点还是必需位点所致。我们表明，通过根据随机选择的患病同胞中是否存在关联标记等位基因对家系进行划分，计算对数优势分数，然后计算异质性统计量，我们可以区分连锁数据是来自易感位点还是必需位点。
