A family-based study design is commonly used in gene mapping studies of complex human diseases. Most family-based studies use the transmission of alleles to assess evidence of association. It is generally believed that the transmission disequilibrium test (TDT) is robust against spurious association due to population stratification or admixture. While this is true when population stratification is due to discrete population structure, one should use the TDT-type methods with caution when they are applied to admixed populations in which population structure exists in local genomic regions. In a recently admixed population, such as African Americans and Hispanic Americans, the linkage disequilibrium coefficient between a marker and disease loci in the parental generation contains a spurious component from the admixture process. In this paper, we show that the general belief that family-based design would guard against spurious association caused by population stratification does not always hold in admixed populations. It is safe to use the TDT as a test of association when population stratification is due to global genome ancestry difference. However, when population stratification is due to local ancestry difference in certain genomic regions, the use of the TDT as a test of association can lead to spurious association. Second, we present a statistical framework for fine mapping of disease-associated genetic variants in admixed families. Unlike the TDT and other family-based association tests, this method does not rely on transmission disequilibrium and therefore can control local ancestry difference between transmitted and untransmitted alleles. Through simulations, we show that this method can control type I error rates under a wide range of population stratification mechanisms.

中文翻译：

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混合家庭中的基因作图：关于传输不平衡测试和可能解决方案的解释性注意事项。

基于家庭的研究设计通常用于复杂人类疾病的基因作图研究。大多数基于家庭的研究都使用等位基因的传播来评估关联的证据。通常认为，传输不平衡测试（TDT）能够有效抵抗由于人口分层或混合造成的虚假关联。当人口分层是由于离散的人口结构而造成的时，这是正确的，但当将TDT型方法应用于当地基因组区域中存在人口结构的混合人口时，应谨慎使用。在最近混合的人群中，例如非裔美国人和西班牙裔美国人，父母代中标记物和疾病位点之间的连锁不平衡系数包含来自混合过程的虚假成分。在本文中，我们证明，基于家庭的设计可以防止由于人口分层而造成的虚假联想的普遍信念并不总是适用于混合人口。当群体分层归因于全球基因组血统差异时，使用TDT作为关联测试是安全的。但是，当人口分层是由于某些基因组区域中本地血统的差异而引起的，使用TDT作为关联测试可能会导致虚假关联。其次，我们提出了一个统计框架，用于在混合家庭中对疾病相关的遗传变异进行精细定位。与TDT和其他基于家族的关联测试不同，此方法不依赖于传输不平衡，因此可以控制已传输和未传输等位基因之间的本地血统差异。通过模拟，