title: The Central Role of KNG1 Gene as a Genetic Determinant of Coagulation Pathway-Related Traits: Exploring Metaphenotypes.
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.
authors.affiliation: Unit of Genomics of Complex Diseases, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Helena
authors.identifier: http://orcid.org/0000-0002-1036-7928
authors.initials: H
authors.lastname: Brunel
authors.affiliation: B2SLab, Departament d'Enginyeria de Sistemes, Automàtica i Informàtica Industrial, Universitat Politècnica de Catalunya (UPC), Barcelona, Spain.
authors.forename: Raimon
authors.initials: R
authors.lastname: Massanet
authors.affiliation: Unit of Genomics of Complex Diseases, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Martinez-Perez
authors.affiliation: Unit of Genomics of Complex Diseases, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Andrey
authors.initials: A
authors.lastname: Ziyatdinov
authors.affiliation: Unit of Genomics of Complex Diseases, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Martin-Fernandez
authors.affiliation: Thrombosis and Haemostasis Unit, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Souto
authors.affiliation: Thrombosis and Haemostasis Unit, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Perera
authors.affiliation: Unit of Genomics of Complex Diseases, Sant Pau Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Soria
mesh_terms: D001777:Blood Coagulation; D060752:Fetuin-B / Q000235:genetics; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007704:Kininogens / Q000235:genetics*; D008962:Models, Theoretical; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D011506:Proteins / Q000235:genetics; D019851:Thrombophilia / Q000235:genetics* / Q000473:pathology; D000099053:Histidine-Rich Glycoprotein
chemical_list: C504687:FETUB protein, human; D060752:Fetuin-B; C000591034:KNG1 protein, human; D007704:Kininogens; D011506:Proteins; D000099053:Histidine-Rich Glycoprotein