Accounting for linkage in family-based tests of association with missing parental genotypes
Accounting for linkage in family-based tests of association with missing parental genotypes
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DOI：
10.1086/378779
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发表时间：
2003-11-01
影响因子：
9.8
通讯作者：
Kaplan, NL
中科院分区：
文献类型：
--
作者：
Martin, ER;Bass, MP;Kaplan, NL
在复杂疾病的研究中，一个常见的范例是在通过连锁分析确定的区域中的标记处进行关联分析，以试图缩小感兴趣的区域。在精细定位研究中，经常使用基于父母向受影响后代传播的关联的家庭测试。然而，对于迟发性疾病，亲本基因型往往缺失。在没有父母基因型的情况下，基于家庭的测试要么比较患病个体与其未患病同胞的等位基因频率，要么使用同胞来推断缺失的父母基因型。后一种方法的一个例子是在计算机程序TRANSMIT中实现的分数测试。在TRANSMIT中缺失亲本基因型的推断假设从亲本到受影响的兄弟姐妹的传播是独立的，这在没有连锁时是合适的。然而，使用计算机模拟，我们表明，当标记和疾病位点是连锁的，数据集由多个受影响的兄弟姐妹的家庭，这种假设导致在标记和疾病等位基因之间没有关联的零假设下的得分统计偏差。这种偏见导致膨胀的I型错误率的得分测试在区域的联系。我们提出了一种新的测试关联在连锁（APL）的存在下，正确推断缺失的父母基因型的连锁区域估计身份的下降参数，调整父母之间的相关性传输到受影响的兄弟姐妹。在模拟数据中，我们证明了APL测试的有效性下的零假设没有关联，并表明该测试可以更强大的系谱不平衡检验和基于家庭的关联检验。作为一个例子，我们比较了在帕金森病家族的候选基因研究中的测试性能。
In studies of complex diseases, a common paradigm is to conduct association analysis at markers in regions identified by linkage analysis, to attempt to narrow the region of interest. Family-based tests for association based on parental transmissions to affected offspring are often used in fine-mapping studies. However, for diseases with late onset, parental genotypes are often missing. Without parental genotypes, family-based tests either compare allele frequencies in affected individuals with those in their unaffected siblings or use siblings to infer missing parental genotypes. An example of the latter approach is the score test implemented in the computer program TRANSMIT. The inference of missing parental genotypes in TRANSMIT assumes that transmissions from parents to affected siblings are independent, which is appropriate when there is no linkage. However, using computer simulations, we show that, when the marker and disease locus are linked and the data set consists of families with multiple affected siblings, this assumption leads to a bias in the score statistic under the null hypothesis of no association between the marker and disease alleles. This bias leads to an inflated type I error rate for the score test in regions of linkage. We present a novel test for association in the presence of linkage (APL) that correctly infers missing parental genotypes in regions of linkage by estimating identity-by-descent parameters, to adjust for correlation between parental transmissions to affected siblings. In simulated data, we demonstrate the validity of the APL test under the null hypothesis of no association and show that the test can be more powerful than the pedigree disequilibrium test and family-based association test. As an example, we compare the performance of the tests in a candidate-gene study in families with Parkinson disease.