The Central Role of KNG1 Gene as a Genetic Determinant of Coagulation Pathway-Related Traits: Exploring Metaphenotypes
Por:
Brunel H, Massanet R, Martinez-Perez A, Ziyatdinov A, Martin-Fernandez L, Souto JC, Perera A and Soria JM
Publicada:
22 dic 2016
Ahead of Print:
22 dic 2016
Resumen:
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.
Filiaciones:
Brunel H:
Unit of Genomics of Complex Diseases, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain
Massanet R:
B2SLab, Departament d'Enginyeria de Sistemes, Automàtica i Informàtica Industrial, Universitat Politècnica de Catalunya (UPC), Barcelona, Spain
Martinez-Perez A:
Unit of Genomics of Complex Diseases, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain
Ziyatdinov A:
Unit of Genomics of Complex Diseases, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain
Martin-Fernandez L:
Unit of Genomics of Complex Diseases, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain
Souto JC:
Thrombosis and Haemostasis Unit, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain
Perera A:
Thrombosis and Haemostasis Unit, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain
Soria JM:
Unit of Genomics of Complex Diseases, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain
Open Access
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