A Clustered Multiclass Likelihood-Ratio Ensemble Method for Family-Based Association Analysis Accounting for Phenotypic Heterogeneity.
A Clustered Multiclass Likelihood-Ratio Ensemble Method for Family-Based Association Analysis Accounting for Phenotypic Heterogeneity.
复制标题
用于考虑表型异质性的基于家族的关联分析的聚类多类似然比集成方法。
DOI：
10.1002/gepi.21987
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发表时间：
2016-09
影响因子：
2.1
通讯作者：
Lu Q
中科院分区：
文献类型：
--
作者：
Wen Y;Lu Q
尽管有令人信服的证据表明，复杂疾病的遗传病因在亚表型组中可能存在异质性，但在复杂疾病的遗传关联分析中，很少有人关注表型异质性。如果具有相似临床表现的亚表型具有异质的潜在遗传病因，则在关联分析中简单地忽略表型异质性可能会导致遗传效应的估计减弱和关联测试的功效较低。为了促进基于家族的关联分析考虑到表型异质性，我们提出了一种聚类多类似然比集成（CMLRE）方法。所提出的方法提供了另一种方法来模拟疾病结果和遗传变异之间的复杂关系。它允许疾病亚表型的异质遗传原因，并且可以应用于各种谱系结构。通过模拟，我们发现 CMLRE 在各种潜在疾病场景中的表现优于常用策略。我们进一步将 CMLRE 应用于识别控制口裂基因和相互作用联盟 (ICOC) 的基于家族的数据集，以研究易导致口裂亚表型的遗传变异和相互作用。分析表明，非综合征性唇裂（CL）和唇裂伴腭（CLP）这两种亚表型具有相似的遗传病因，而单纯腭裂（CP）则有其自己的遗传机制。分析进一步显示，rs10863790 (IRF6)、rs7017252 (8q24) 和 rs7078160 (VAX1) 与 CL/CLP 共同相关，而 rs7969932 (TBK1)、rs227731 (17q22) 和 rs2141765 (TBK1) 共同与 CP 相关。
Although compelling evidence suggests that the genetic etiology of complex diseases could be heterogeneous in subphenotype groups, little attention has been paid to phenotypic heterogeneity in genetic association analysis of complex diseases. Simply ignoring phenotypic heterogeneity in association analysis could result in attenuated estimates of genetic effects and low power of association tests if subphenotypes with similar clinical manifestations have heterogeneous underlying genetic etiologies. To facilitate the family-based association analysis allowing for phenotypic heterogeneity, we propose a clustered multiclass likelihood-ratio ensemble (CMLRE) method. The proposed method provides an alternative way to model the complex relationship between disease outcomes and genetic variants. It allows for heterogeneous genetic causes of disease subphenotypes and can be applied to various pedigree structures. Through simulations, we found CMLRE outperformed the commonly adopted strategies in a variety of underlying disease scenarios. We further applied CMLRE to a family-based dataset from the International Consortium to Identify Genes and Interactions Controlling Oral Clefts (ICOC) to investigate the genetic variants and interactions predisposing to subphenotypes of oral clefts. The analysis suggested that two subphenotypes, nonsyndromic cleft lip without palate (CL) and cleft lip with palate (CLP), shared similar genetic etiologies, while cleft palate only (CP) had its own genetic mechanism. The analysis further revealed that rs10863790 (IRF6), rs7017252 (8q24), and rs7078160 (VAX1) were jointly associated with CL/CLP, while rs7969932 (TBK1), rs227731 (17q22), and rs2141765 (TBK1) jointly contributed to CP.