Abstract
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.
Highlights
Considerable efforts have been invested to evaluate hundreds of genetic variants associated with human traits
APTT measures the combined activity of several clotting factors in the intrinsic and common coagulation pathways [10], the present genetic studies on Activated Prothrombin Time (aPTT) consider it as an univariate model without considering pleiotropic effects [11]. Another example of exploiting the genetic information of different traits comes from the GAIT (Genetic Analysis of Idiopathic Thrombophilia) Project, where we demonstrated that coagulation factors FVIII and vWF are genetically correlated with thrombotic disease [12]
To illustrate the relevance of these findings, they were compared with metaphenotypes obtained with a Principal Components Analysis (PCA)-based approach and with univariate GWAS applied to the original phenotypes
Summary
Considerable efforts have been invested to evaluate hundreds of genetic variants associated with human traits Despite these efforts, the loci that have been identified only explain a small proportion of the total phenotypic variance. The normal physiological process underlying thrombosis is complex and many of its components are involved in the coagulation and fibrinolysis pathways. These components form a collection of intermediate phenotypes that are generally measured in the study of thrombosis. These intermediate phenotypes may reflect more directly the effects from causal genes than disease status. They are less genetically complex and more strongly associated with susceptibility loci
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
