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Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.

TitleRare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.
Publication TypeJournal Article
Year of Publication2015
AuthorsHuffman, JE, de Vries, PS, Morrison, AC, Sabater-Lleal, M, Kacprowski, T, Auer, PL, Brody, JA, Chasman, DI, Chen, M-H, Guo, X, Lin, L-A, Marioni, RE, Müller-Nurasyid, M, Yanek, LR, Pankratz, N, Grove, ML, de Maat, MPM, Cushman, M, Wiggins, KL, Qi, L, Sennblad, B, Harris, SE, Polasek, O, Riess, H, Rivadeneira, F, Rose, LM, Goel, A, Taylor, KD, Teumer, A, Uitterlinden, AG, Vaidya, D, Yao, J, Tang, W, Levy, D, Waldenberger, M, Becker, DM, Folsom, AR, Giulianini, F, Greinacher, A, Hofman, A, Huang, C-C, Kooperberg, C, Silveira, A, Starr, JM, Strauch, K, Strawbridge, RJ, Wright, AF, McKnight, B, Franco, OH, Zakai, N, Mathias, RA, Psaty, BM, Ridker, PM, Tofler, GH, Völker, U, Watkins, H, Fornage, M, Hamsten, A, Deary, IJ, Boerwinkle, E, Koenig, W, Rotter, JI, Hayward, C, Dehghan, A, Reiner, AP, O'Donnell, CJ, Smith, NL
Date Published2015 Sep 10
KeywordsCohort Studies, Factor VII, Factor VIII, Fibrinogen, Gene Frequency, Genetic Association Studies, Genetic Variation, Humans, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, von Willebrand Factor
Abstract<p>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.</p>
Alternate JournalBlood
PubMed ID26105150
PubMed Central IDPMC4566813
Grant ListBB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
CZB/4/505 / / Chief Scientist Office / United Kingdom
ETM/55 / / Chief Scientist Office / United Kingdom
G0700704 / / Medical Research Council / United Kingdom
MC_PC_U127561128 / / Medical Research Council / United Kingdom
MR/K026992/1 / / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
UM1 CA182913 / CA / NCI NIH HHS / United States
ePub date: 
2015 Jun 23