Challenges of linkage analysis in the era of whole-genome sequencing.
Challenges of linkage analysis in the era of whole-genome sequencing.
复制标题
全基因组测序时代连锁分析的挑战。
DOI：
10.1002/gepi.21832
复制
发表时间：
2014
影响因子：
2.1
通讯作者：
Edwards,KarenL
中科院分区：
文献类型：
--
作者：
Santorico,StephanieA;Edwards,KarenL
全基因组测序(WGS)正在成为研究复杂性状遗传学的一种负担得起的技术。对于任何新技术，实验设计和统计方法，无论是旧的还是新的，都必须进行评估。一种重新引起人们兴趣的设计是家庭的使用。遗传分析讲习班18提供了评价应用于WGS数据的统计方法以进行基于家庭的研究的机会。我们总结了在WGS背景下使用链接的五个贡献的结果。研究人员采取了不同的方法，包括评估经典两点连锁的假阳性率，异质性对连锁和关联测试的影响，以及使用连锁来集中关联测试。我们描述了每个贡献的主要发现，并注意到对于从事家庭设计的人或特定于WGS数据的挑战；例如，表型定义的选择、协变量调整和纵向数据的使用可能会产生不同的结果，从而使比较具有挑战性。我们详细介绍了WGS带来的新问题，例如经典的两点参数连锁分析的全基因组假阳性率上升，多点计算的计算要求，以及如何最好地利用连锁来聚焦关联测试缺乏清晰度。最后，我们评论了连锁何时可能对WGS有帮助，强调了需要进一步研究的地方；例如，尽管连锁分析在研究大效应的罕见变异方面已经成功，但如何在中等效应的罕见变异的背景下最好地利用家族信息仍然是一个悬而未决的研究问题。
Whole‐genome sequencing (WGS) is becoming an affordable technology for the study of the genetics of complex traits. With any new technology, experimental designs and statistical methods, both old and new, must be evaluated. One design seeing a resurgence of interest is the use of families. Genetic Analysis Workshop 18 provided the opportunity to evaluate statistical methods applied to WGS data for family‐based studies. We summarize the results of five contributions that used linkage in the context of WGS. The investigators took differing approaches, including assessment of false‐positive rates in classic two‐point linkage, the effects of heterogeneity on linkage and association tests, and the use of linkage to focus association tests. We describe the primary findings of each contribution and note challenges that are not new to those working in family designs or specific to WGS data; for example, choice of phenotype definition, covariate adjustment, and use of longitudinal data may produce different results, making comparisons challenging. We detail new issues brought about by WGS, such as the elevated genome‐wide false‐positive rate for classic two‐point parametric linkage analysis, computational demands in multipoint calculations, and lack of clarity in how to best use linkage to focus association testing. Finally, we comment on when linkage may be helpful for WGS, highlighting where additional research is needed; for example, although linkage analysis has been successful in the study of rare variants of large effect, how to best use family information in the context of rare variants of moderate effect remains an open research question.