The Central Role of KNG1 Gene as a Genetic Determinant of Coagulation Pathway-Related Traits: Exploring Metaphenotypes.
The Central Role of KNG1 Gene as a Genetic Determinant of Coagulation Pathway-Related Traits: Exploring Metaphenotypes.
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DOI：
10.1371/journal.pone.0167187
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Soria JM
中科院分区：
文献类型：
--
作者：
Brunel H;Massanet R;Martinez-Perez A;Ziyatdinov A;Martin-Fernandez L;Souto JC;Perera A;Soria JM
传统的单一性状的遗传学研究可能无法检测复杂疾病中涉及的多效性效应。为了检测在同一生物过程中涉及的几种表型之间存在的相关性，我们引入了一种原始的方法来分析在全基因组关联研究中涉及凝血级联反应的相关表型集。该方法包括两个阶段。首先，我们定义新的表型元变量（原始表型的线性组合），命名为元表型，通过应用独立成分分析相关表型（即凝血途径相关蛋白质的水平）的多变量分析。所得到的元表型整合了关于潜在生物过程（即血栓/凝块形成）的信息。其次，我们利用基于家族的全基因组关联研究来确定影响这些元表型的遗传因素，从而确定血栓形成的风险。我们的研究利用了GAIT项目（特发性血栓形成倾向的遗传分析）的数据。我们获得了15个元表型，表现出显着的遗传力，从0.2到0.7不等。这些结果表明遗传因素在这些性状变异中的重要性。我们发现4个元表型与SNP有显著相关性。最相关的是那些映射在HRG，FETUB和KNG 1基因附近的区域。我们的研究结果是挑衅性的，因为他们表明，KNG 1基因座起着核心作用，作为整个凝血途径和血栓/凝块形成的遗传决定因素。通过元表型整合来自多个相关测量的数据是阐明复杂疾病背后隐藏的遗传机制的一种有前途的方法。
Traditional genetic studies of single traits may be unable to detect the pleiotropic effects involved in complex diseases. To detect the correlation that exists between several phenotypes involved in the same biological process, we introduce an original methodology to analyze sets of correlated phenotypes involved in the coagulation cascade in genome-wide association studies. The methodology consists of a two-stage process. First, we define new phenotypic meta-variables (linear combinations of the original phenotypes), named metaphenotypes, by applying Independent Component Analysis for the multivariate analysis of correlated phenotypes (i.e. the levels of coagulation pathway–related proteins). The resulting metaphenotypes integrate the information regarding the underlying biological process (i.e. thrombus/clot formation). Secondly, we take advantage of a family based Genome Wide Association Study to identify genetic elements influencing these metaphenotypes and consequently thrombosis risk. Our study utilized data from the GAIT Project (Genetic Analysis of Idiopathic Thrombophilia). We obtained 15 metaphenotypes, which showed significant heritabilities, ranging from 0.2 to 0.7. These results indicate the importance of genetic factors in the variability of these traits. We found 4 metaphenotypes that showed significant associations with SNPs. The most relevant were those mapped in a region near the HRG, FETUB and KNG1 genes. Our results are provocative since they show that the KNG1 locus plays a central role as a genetic determinant of the entire coagulation pathway and thrombus/clot formation. Integrating data from multiple correlated measurements through metaphenotypes is a promising approach to elucidate the hidden genetic mechanisms underlying complex diseases.
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