JBASE: Joint Bayesian Analysis of Subphenotypes and Epistasis.
JBASE: Joint Bayesian Analysis of Subphenotypes and Epistasis.
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DOI：
10.1093/bioinformatics/btv504
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发表时间：
2016-01-15
期刊：
影响因子：
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通讯作者：
Goldenberg A
中科院分区：
文献类型：
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作者：
Colak R;Kim T;Kazan H;Oh Y;Cruz M;Valladares-Salgado A;Peralta J;Escobedo J;Parra EJ;Kim PM;Goldenberg A
动机：基因分型和全基因组关联研究的快速发展使得在个体标记的分辨率上发现了许多新的基因型-表型关联。然而，这些关联只能解释大多数疾病理论上估计的遗传性的一小部分。在这项工作中，我们提出了一个称为JBASE的综合混合模型：亚表型和上位性的联合贝叶斯分析。JBASE探讨了遗传缺失的两个主要原因：遗传变异之间的相互作用，一种称为上位性的现象和表型异质性，通过亚表型来解决。结果：我们在各种情况下的广泛模拟反复表明，JBASE可以高精度地识别真正的潜在亚表型，包括它们的相关变体和它们的相互作用。在存在表型异质性的情况下，与五种最先进的方法相比，JBASE具有更高的功率和更低的1型误差。我们将该方法应用于来自墨西哥的2型糖尿病患者样本，发现了两个新的上位模块，每个模块包括两个基因座，它们定义了两个以体重指数和腰臀比差异为特征的亚表型。我们成功地在来自墨西哥的独立数据集中复制了这些亚表型和上位模块，并使用不同的平台进行基因分型。可用性和实现：JBASE是用c++实现的，在Linux上支持，可以在http://www.cs.toronto.edu/ ~ goldenberg/JBASE/ JBASE .tar.gz上获得。本研究的基因型数据经Siglo XXI医学中心伦理审查委员会批准后可获得。请通过mcruzl@yahoo.com与Miguel Cruz博士联系以获得申请方面的帮助。补充信息：补充数据可在Bioinformatics在线获取。
Motivation: Rapid advances in genotyping and genome-wide association studies have enabled the discovery of many new genotype–phenotype associations at the resolution of individual markers. However, these associations explain only a small proportion of theoretically estimated heritability of most diseases. In this work, we propose an integrative mixture model called JBASE: joint Bayesian analysis of subphenotypes and epistasis. JBASE explores two major reasons of missing heritability: interactions between genetic variants, a phenomenon known as epistasis and phenotypic heterogeneity, addressed via subphenotyping. Results: Our extensive simulations in a wide range of scenarios repeatedly demonstrate that JBASE can identify true underlying subphenotypes, including their associated variants and their interactions, with high precision. In the presence of phenotypic heterogeneity, JBASE has higher Power and lower Type 1 Error than five state-of-the-art approaches. We applied our method to a sample of individuals from Mexico with Type 2 diabetes and discovered two novel epistatic modules, including two loci each, that define two subphenotypes characterized by differences in body mass index and waist-to-hip ratio. We successfully replicated these subphenotypes and epistatic modules in an independent dataset from Mexico genotyped with a different platform. Availability and implementation: JBASE is implemented in C++, supported on Linux and is available at http://www.cs.toronto.edu/∼goldenberg/JBASE/jbase.tar.gz. The genotype data underlying this study are available upon approval by the ethics review board of the Medical Centre Siglo XXI. Please contact Dr Miguel Cruz at mcruzl@yahoo.com for assistance with the application. Contact: anna.goldenberg@utoronto.ca Supplementary information: Supplementary data are available at Bioinformatics online.