Evaluating genetic heterogeneity in complex disorders
Evaluating genetic heterogeneity in complex disorders
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DOI：
10.1159/000066195
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发表时间：
2002-01-01
期刊：
影响因子：
1.8
通讯作者：
Greenberg, DA
中科院分区：
文献类型：
--
作者：
Pal, DK;Greenberg, DA
目的：混合物检验通常用于连锁分析，以考虑遗传异质性，并产生对（a）分离连锁疾病基因的家庭比例的估计。在复杂疾病中，混合物检验的假设被违反。因此，我们探讨了如何估计的一个涉及到一个复杂的疾病在人口或数据集的真实比例的家庭。方法：我们模拟了一个双位点异质性模型，并改变了遗传参数、确定方案和表型频率。结果：在这个模型中，a几乎总是被高估，少则5%，多则60%。这种偏倚主要归因于：（1）家族内的异质性，这是由于确定了有许多患病成员的家族或分析了密集的家系而引起的;（2）低信息量，这发生在患病率降低的情况下;（3）连锁和非连锁家族中连锁证据的差异。这种偏差也受分析表型频率的影响，但只有当连锁位点是显性的，非连锁位点是隐性的。结论：我们的结论是，在复杂的疾病，混合物测试有更大的价值，在检测连锁比估计的比例，在一个数据集中的连锁家庭。版权所有（C）2002 S. Karger AG，巴塞尔。
Objectives: The Admixture test is routinely used in linkage analysis to take account of genetic heterogeneity, and yields an estimate of the proportion of families (a) segregating the linked disease gene. In complex disorders, the assumptions of the Admixture test are violated. We therefore explore how the estimate of a relates to the true proportion of linked families with a complex disorder in a population or dataset. Methods: We simulated a two-locus heterogeneity model and varied genetic parameters, ascertainment scheme and phenocopy frequency. Results: In this model, a is almost always overestimated, by as little as 5% to as much as 60%. The bias is largely attributable to (1) intrafamilial heterogeneity arising from ascertainment of families with many affected members or from analysis of dense pedigrees; (2) low informativeness, which occurs in the presence of reduced penetrance; and (3) differences in the evidence for linkage in linked and unlinked families. This bias is also affected by the analysis phenocopy frequency, but only if the linked locus is dominant and the unlinked locus is recessive. Conclusions: We conclude that, in complex diseases, the Admixture test has greater value in detecting linkage than in estimating the proportion of linked families in a dataset. Copyright (C) 2002 S. Karger AG, Basel.