Boehnke M, Langefeld C D
Department of Biostatistics, University of Michigan, Ann Arbor, MI USA.
Am J Hum Genet. 1998 Apr;62(4):950-61. doi: 10.1086/301787.
Family-based tests of association provide the opportunity to test for an association between a disease and a genetic marker. Such tests avoid false-positive results produced by population stratification, so that evidence for association may be interpreted as evidence for linkage or causation. Several methods that use family-based controls have been proposed, including the haplotype relative risk, the transmission-disequilibrium test, and affected family-based controls. However, because these methods require genotypes on affected individuals and their parents, they are not ideally suited to the study of late-onset diseases. In this paper, we develop several family-based tests of association that use discordant sib pairs (DSPs) in which one sib is affected with a disease and the other sib is not. These tests are based on statistics that compare counts of alleles or genotypes or that test for symmetry in tables of alleles or genotypes. We describe the use of a permutation framework to assess the significance of these statistics. These DSP-based tests provide the same general advantages as parent-offspring trio-based tests, while being applicable to essentially any disease; they may also be tailored to particular hypotheses regarding the genetic model. We compare the statistical properties of our DSP-based tests by computer simulation and illustrate their use with an application to Alzheimer disease and the apolipoprotein E polymorphism. Our results suggest that the discordant-alleles test, which compares the numbers of nonmatching alleles in DSPs, is the most powerful of the tests we considered, for a wide class of disease models and marker types. Finally, we discuss advantages and disadvantages of the DSP design for genetic association mapping.
基于家系的关联检验为检测疾病与基因标记之间的关联提供了机会。此类检验可避免群体分层产生的假阳性结果，因此关联证据可被解释为连锁或因果关系的证据。已经提出了几种使用基于家系的对照的方法，包括单倍型相对风险、传递不平衡检验和基于患病家系的对照。然而，由于这些方法需要患病个体及其父母的基因型，它们并不非常适合用于迟发性疾病的研究。在本文中，我们开发了几种基于家系的关联检验，这些检验使用不一致同胞对（DSPs），其中一个同胞患有某种疾病而另一个同胞未患病。这些检验基于比较等位基因或基因型计数或检验等位基因或基因型表格中对称性的统计量。我们描述了使用置换框架来评估这些统计量的显著性。这些基于DSP的检验具有与基于亲代-子代三联体的检验相同的一般优势，同时基本上适用于任何疾病；它们也可以针对关于遗传模型的特定假设进行调整。我们通过计算机模拟比较了基于DSP的检验的统计特性，并通过应用于阿尔茨海默病和载脂蛋白E多态性来说明它们的用途。我们的结果表明，比较DSP中不匹配等位基因数量的不一致等位基因检验，对于广泛的疾病模型和标记类型来说，是我们所考虑的检验中最具效力的。最后，我们讨论了DSP设计在基因关联图谱绘制中的优缺点。
