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


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.

SUBMITTER: Huffman JE 

PROVIDER: S-EPMC4566813 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

Huffman Jennifer E JE   de Vries Paul S PS   Morrison Alanna C AC   Sabater-Lleal Maria M   Kacprowski Tim T   Auer Paul L PL   Brody Jennifer A JA   Chasman Daniel I DI   Chen Ming-Huei MH   Chen Ming-Huei MH   Guo Xiuqing X   Lin Li-An LA   Marioni Riccardo E RE   Müller-Nurasyid Martina M   Yanek Lisa R LR   Pankratz Nathan N   Grove Megan L ML   de Maat Moniek P M MP   Cushman Mary M   Wiggins Kerri L KL   Qi Lihong L   Sennblad Bengt B   Harris Sarah E SE   Polasek Ozren O   Riess Helene H   Rivadeneira Fernando F   Rose Lynda M LM   Goel Anuj A   Taylor Kent D KD   Teumer Alexander A   Uitterlinden André G AG   Vaidya Dhananjay D   Yao Jie J   Tang Weihong W   Levy Daniel D   Waldenberger Melanie M   Becker Diane M DM   Folsom Aaron R AR   Giulianini Franco F   Greinacher Andreas A   Hofman Albert A   Huang Chiang-Ching CC   Kooperberg Charles C   Silveira Angela A   Starr John M JM   Strauch Konstantin K   Strawbridge Rona J RJ   Wright Alan F AF   McKnight Barbara B   Franco Oscar H OH   Zakai Neil N   Mathias Rasika A RA   Psaty Bruce M BM   Ridker Paul M PM   Tofler Geoffrey H GH   Völker Uwe U   Watkins Hugh H   Fornage Myriam M   Hamsten Anders A   Deary Ian J IJ   Boerwinkle Eric E   Koenig Wolfgang W   Rotter Jerome I JI   Hayward Caroline C   Dehghan Abbas A   Reiner Alex P AP   O'Donnell Christopher J CJ   Smith Nicholas L NL  

Blood 20150623 11


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 concentrati  ...[more]

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