Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF
Year: 2015
Type: article
Study design: Observational Study
Abstract: Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.
Source: Blood
Authors: Jennifer E. Huffman, Paul S. de Vries, Alanna C. Morrison, Maria Sabater-Lleal, Tim Kacprowski, Paul L. Auer, Jennifer A. Brody, Daniel I. Chasman, Ming-Huei Chen, Xiuqing Guo, Li-An Lin, Riccardo E. Marioni, Martina Müller-Nurasyid, Lisa R. Yanek, Nathan Pankratz, Megan L. Grove, Moniek P. M. de Maat, Mary Cushman, Kerri L. Wiggins, Lihong Qi, Bengt Sennblad, Sarah E. Harris, Ozren Polasek, Helene Riess, Fernando Rivadeneira, Lynda M. Rose, Anuj Goel, Kent D. Taylor, Alexander Teumer, André G. Uitterlinden, Dhananjay Vaidya, Jie Yao, Weihong Tang, Daniel Levy, Melanie Waldenberger, Diane M. Becker, Aaron R. Folsom, Franco Giulianini, Andreas Greinacher, Albert Hofman, Chiang-Ching Huang, Charles Kooperberg, Angela Silveira, John M. Starr, Konstantin Strauch, Rona J. Strawbridge, Alan F. Wright, Barbara McKnight, Oscar H. Franco, Neil Zakai, Rasika A. Mathias, Bruce M. Psaty, Paul M. Ridker, Geoffrey H. Tofler, Uwe Völker, Hugh Watkins, Myriam Fornage, Anders Hamsten, Ian J. Deary, Eric Boerwinkle, Wolfgang Koenig, Jerome I. Rotter, Caroline Hayward, Abbas Dehghan, Alex P. Reiner, Christopher J. O’Donnell, Nicholas L. Smith
Institutions: National Institutes of Health, National Heart, Lung, and Blood Institute, Framingham Heart Study, Institute of Genetics and Cancer, MRC Human Genetics Unit, National Heart, Lung, and Blood Institute Division of Intramural Research, University of Edinburgh, Erasmus MC, The University of Texas Health Science Center at Houston, Karolinska Institutet, Universität Greifswald, University of Wisconsin–Milwaukee, University of Washington, Brigham and Women's Hospital, Harvard University, Boston University, University of California, Los Angeles, The Lundquist Institute, UCLA Medical Center, Harbor–UCLA Medical Center, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Queensland, Helmholtz Munich, German Centre for Cardiovascular Research, Ludwig-Maximilians-Universität München, Johns Hopkins University, Johns Hopkins Medicine, University of Minnesota, University of Vermont, University of California, Davis, Science for Life Laboratory, University of Split, Universität Ulm, John Radcliffe Hospital, University of Oxford, Universitätsmedizin Greifswald, Fred Hutch Cancer Center, Alzheimer Scotland, Group Health Cooperative, Kaiser Permanente Washington Health Research Institute, The University of Sydney, Royal North Shore Hospital, Baylor College of Medicine, Deutsches Herzzentrum München, Technical University of Munich, VA Office of Research and Development, Seattle Epidemiologic Information and Research Center
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Institutes of Health, Medical Research Council, Biotechnology and Biological Sciences Research Council, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: FHCRC High-Performance Computing Cluster, Rare variants and NHLBI traits in deeply phenotyped cohorts, G232264632, G297113894, A Family-based Exome Sequencing Approach to Identify Platelet Aggregation Genes, UCLA Clinical and Translational Science Institute, G4429312988, G4641403149, G5067462658, Epidemiology of Venous Thrombosis and Pulmonary Embolism, A genome-wide association study of non-pathological cognitive ageing, G814381192, Cancer Center Support Grant, Diabetes Research Center (DRC)
OpenAlex ID: W1934803189