Yang Fan, Thomas Duncan C
Department of Preventive Medicine, University of Southern California, Los Angeles, USA.
Hum Hered. 2011;71(4):209-20. doi: 10.1159/000328193. Epub 2011 Jul 2.
Multiple rare variants have been suggested as accounting for some of the associations with common single nucleotide polymorphisms identified in genome-wide association studies or possibly some of the as yet undiscovered heritability. We consider the power of various approaches to designing substudies aimed at using next-generation sequencing technologies to discover novel variants and to select some subsets that are possibly causal for genotyping in the original case-control study and testing for association using various weighted sum indices. We find that the selection of variants based on the statistical significance of the case-control difference in the subsample yields good power for testing rare variant indices in the main study, and that multivariate models including both the summary index of rare variants and the associated common single nucleotide polymorphisms can distinguish which is the causal factor. By simulation, we explore the effects of varying the size of the discovery subsample, choice of index, and true causal model.
多个罕见变异被认为可以解释全基因组关联研究中所识别的一些与常见单核苷酸多态性的关联，或者可能解释一些尚未被发现的遗传力。我们考虑了各种方法在设计子研究时的效能，这些子研究旨在利用新一代测序技术发现新的变异，并选择一些可能具有因果关系的子集，以便在最初的病例对照研究中进行基因分型，并使用各种加权和指数来检验关联性。我们发现，基于子样本中病例对照差异的统计显著性来选择变异，在主要研究中对检验罕见变异指数具有良好的效能，并且包括罕见变异的汇总指数和相关常见单核苷酸多态性的多变量模型能够区分哪个是因果因素。通过模拟，我们探讨了改变发现子样本大小、指数选择和真实因果模型的影响。
