Methods for detection of parent-of-origin effects in genetic studies of case-parents triads
Methods for detection of parent-of-origin effects in genetic studies of case-parents triads
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DOI：
10.1086/302466
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发表时间：
1999-07-01
影响因子：
9.8
通讯作者：
Weinberg, CR
中科院分区：
文献类型：
--
作者：
Weinberg, CR
当受影响的先证者和他们的生物学父母在候选基因或标记基因分型时，所得到的病例-父母-三联体数据能够在存在关联的情况下进行强有力的连锁检验。当在这样的研究中检测到连锁不平衡时，研究者可能希望进一步寻找可能的亲本效应。例如，如果仅限于父亲的传递/不平衡检验具有统计学显著性，而仅限于母亲的则不显著，则研究者可能将其解释为母体来源的疾病基因（即印迹）不表达的证据。本报告回顾了现有的方法检测的父源效应，表明每一个可以在某些情况下无效。提出了两种新的方法，基于分层后的父母交配类型和遗传的等位基因的拷贝数的研究中的应用基于似然推理。如果在妊娠期产前没有母体遗传效应，则父母不对称检验是有效的，并提供了对父母来源参数的有效估计。对于可能存在母体对风险的影响的疾病，父母来源似然比检验提供了一个强有力的替代方法。在不同的情况下，基于受人尊敬的人群的模拟显示了这些程序的良好操作特性。
When affected probands and their biological parents are genotyped at a candidate gene or a marker, the resulting case-parents-triad data enable powerful tests for linkage in the presence of association. When linkage disequilibrium has been detected in such a study, the investigator may wish to look further for possible parent-of-origin effects. If, for example, the transmission/disequilibrium test restricted to fathers is statistically significant, whereas that restricted to mothers is not, the investigator might interpret this as evidence for nonexpression of the maternally derived disease gene-that is, imprinting. This report reviews existing methods for detection of parent-of-origin effects, showing that each can be invalid under certain scenarios. Two new methods are proposed, based on application of likelihood-based inference after stratification on both the parental mating type and the inherited number of copies of the allele under study. If there are no maternal genetic effects expressed prenatally during gestation, the parental-asymmetry test is powerful and provides valid estimation of a parent-of-origin parameter. For diseases for which there could be maternal effects on risk, the parent-of-origin likelihood-ratio test provides a robust alternative. Simulations based on an admired population demonstrate good operating characteristics for these procedures, under diverse scenarios.