Although genome‐wide association studies have been widely used to identify associations between complex diseases and genetic variants, standard single‐variant analyses often have limited power when applied to rare variants. To overcome this problem, set‐based methods have been developed with the aim of boosting power by borrowing strength from multiple rare variants. We propose the adaptive hierarchically structured variable selection (HSVS‐A) before test for association of rare variants in a set with continuous or dichotomous phenotypes and to estimate the effect of individual rare variants simultaneously. HSVS‐A has the flexibility to integrate a pairwise weighting scheme, which adaptively induces desirable correlations among variants of similar significance such that we can borrow information from potentially causal and noncausal rare variants to boost power. Simulation studies show that for both continuous and dichotomous phenotypes, HSVS‐A is powerful when there are multiple causal rare variants, either in the same or opposite direction of effect, with the presence of a large number of noncausal variants. We also apply HSVS‐A to the Wellcome Trust Case Control Consortium Crohn's disease data for testing the association of Crohn's disease with rare variants in pathways. HSVS‐A identifies two pathways harboring novel protective rare variants for Crohn's disease.

中文翻译：

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用于稀有变量关联测试的贝叶斯层次结构先验

尽管全基因组关联研究已被广泛用于识别复杂疾病和遗传变异之间的关联，但标准的单变异分析在应用于罕见变异时通常效果有限。为了克服这个问题，已经开发了基于集合的方法，旨在通过从多个稀有变体中借用强度来提高功率。我们建议在测试一组稀有变异与连续或二分类表型的关联之前使用自适应分层结构变量选择 (HSVS-A)，并同时估计单个稀有变异的影响。HSVS-A 具有集成成对加权方案的灵活性，它自适应地在具有相似意义的变体之间诱导出理想的相关性，这样我们就可以从潜在的因果和非因果罕见变体中借用信息来提高能力。模拟研究表明，对于连续表型和二分表型，当存在多个因果罕见变异时，HSVS-A 是强大的，无论是在相同或相反的影响方向上，并且存在大量非因果变异。我们还将 HSVS-A 应用于 Wellcome Trust Case Control Consortium 克罗恩病数据，以测试克罗恩病与途径中罕见变异的关联。HSVS-A 确定了两条途径，其中包含针对克罗恩病的新型保护性罕见变异。当存在多个因果罕见变异时，HSVS-A 是强大的，无论是在相同或相反的效果方向上，并且存在大量非因果变异。我们还将 HSVS-A 应用于 Wellcome Trust Case Control Consortium 克罗恩病数据，以测试克罗恩病与途径中罕见变异的关联。HSVS-A 确定了两条途径，其中包含针对克罗恩病的新型保护性罕见变异。当存在多个因果罕见变异时，HSVS-A 是强大的，无论是在相同或相反的效果方向上，并且存在大量非因果变异。我们还将 HSVS-A 应用于 Wellcome Trust Case Control Consortium 克罗恩病数据，以测试克罗恩病与途径中罕见变异的关联。HSVS-A 确定了两条途径，其中包含针对克罗恩病的新型保护性罕见变异。