1. Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF
- Author
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Wolfgang Koenig, Lynda M. Rose, Konstantin Strauch, Charles Kooperberg, Kent D. Taylor, Aaron R. Folsom, Nathan Pankratz, Daniel I. Chasman, Jie Yao, Sarah E. Harris, Caroline Hayward, Albert Hofman, Bruce M. Psaty, Kerri L. Wiggins, Megan L. Grove, Ming-Huei Chen, Alan F. Wright, Lihong Qi, Jennifer A. Brody, Paul M. Ridker, Ozren Polasek, Mary Cushman, Maria Sabater-Lleal, Eric Boerwinkle, Christopher J. O'Donnell, Tim Kacprowski, Myriam Fornage, Riccardo E. Marioni, Alexander P. Reiner, Franco Giulianini, Alanna C. Morrison, Alexander Teumer, Fernando Rivadeneira, Xiuqing Guo, Hugh Watkins, Oscar H. Franco, Abbas Dehghan, Helene Riess, Melanie Waldenberger, Barbara McKnight, André G. Uitterlinden, Neil A. Zakai, Anders Hamsten, Bengt Sennblad, Jennifer E. Huffman, Paul L. Auer, Uwe Völker, Rasika A. Mathias, Rona J. Strawbridge, Angela Silveira, Moniek P.M. de Maat, Geoffrey H. Tofler, Chiang Ching Huang, Lisa R. Yanek, Andreas Greinacher, Paul S. de Vries, Anuj Goel, Dhananjay Vaidya, Daniel Levy, Jerome I. Rotter, Martina Müller-Nurasyid, Nicholas L. Smith, John M. Starr, Weihong Tang, Li-An Lin, Ian J. Deary, Diane M. Becker, Epidemiology, Hematology, and Internal Medicine
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Candidate gene ,Potassium Channels ,Clinical Sciences ,Immunology ,Nerve Tissue Proteins ,Genome-wide association study ,Potassium Channels, Sodium-Activated ,Cardiorespiratory Medicine and Haematology ,Fibrinogen ,Polymorphism, Single Nucleotide ,Biochemistry ,Thrombosis and Hemostasis ,Cohort Studies ,Paediatrics and Reproductive Medicine ,chemistry.chemical_compound ,Gene Frequency ,Von Willebrand factor ,hemic and lymphatic diseases ,von Willebrand Factor ,medicine ,Humans ,Polymorphism ,Allele frequency ,Genetic Association Studies ,Genetics ,Factor VIII ,biology ,Factor VII ,Genetic Variation ,Single Nucleotide ,Cell Biology ,Hematology ,Minor allele frequency ,chemistry ,Hemostasis ,biology.protein ,medicine.drug - 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) andrare (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.
- Published
- 2015