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

Huffman, Jennifer E., De Vries, Paul S., Morrison, Alanna C., Sabater-Lleal, Maria, Kacprowski, Tim, Auer, Paul L., Brody, Jennifer A., Chasman, Daniel I., Chen, Ming-Huei, Guo, Xiuqing, Lin, Li-An, Marioni, Riccardo E., Muller-Nurasyid, Martina, Yanek, Lisa R., Pankratz, Nathan, Grove, Megan L., De Maat, Moniek P. M., Cushman, Mary, Wiggins, Kerri L., Qi, Lihong, Sennblad, Bengt, Harris, Sarah E., Polasek, Ozren, Riess, Helene, Rivadeneira, Fernando, Rose, Lynda M., Goel, Anuj, Taylor, Kent D., Teumer, Alexander, Uitterlinden, André G., Vaidya, Dhananjay, Yao, Jie, Tang, Weihong, Levy, Daniel, Waldenberger, Melanie, Becker, Diane M., Folsom, Aaron R., Giulianini, Franco, Greinacher, Andreas, Hofman, Albert, Huang, Chiang-Ching, Kooperberg, Charles, Silveira, Angela, Starr, John M., Strauch, Konstantin, Strawbridge, Rona J., Wright, Alan F., McKnight, Barbara, Franco, Oscar H., Zakai, Neil, Mathias, Rasika A., Psaty, Bruce M., Ridker, Paul M., Tofler, Geoffrey H., Völker, Uwe, Watkins, Hugh, Fornage, Myriam, Hamsten, Anders, Deary, Ian J., Boerwinkle, Eric, Koenig, Wolfgang, Rotter, Jerome I., Hayward, Caroline, Dehghan, Abbas, Reiner, Alex P., O'Donnell, Christopher J. and Smith, Nicholas L. (2015) Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. Blood, 126 11: e19-e29. doi:10.1182/blood-2015-02-624551


Author Huffman, Jennifer E.
De Vries, Paul S.
Morrison, Alanna C.
Sabater-Lleal, Maria
Kacprowski, Tim
Auer, Paul L.
Brody, Jennifer A.
Chasman, Daniel I.
Chen, Ming-Huei
Guo, Xiuqing
Lin, Li-An
Marioni, Riccardo E.
Muller-Nurasyid, Martina
Yanek, Lisa R.
Pankratz, Nathan
Grove, Megan L.
De Maat, Moniek P. M.
Cushman, Mary
Wiggins, Kerri L.
Qi, Lihong
Sennblad, Bengt
Harris, Sarah E.
Polasek, Ozren
Riess, Helene
Rivadeneira, Fernando
Rose, Lynda M.
Goel, Anuj
Taylor, Kent D.
Teumer, Alexander
Uitterlinden, André G.
Vaidya, Dhananjay
Yao, Jie
Tang, Weihong
Levy, Daniel
Waldenberger, Melanie
Becker, Diane M.
Folsom, Aaron R.
Giulianini, Franco
Greinacher, Andreas
Hofman, Albert
Huang, Chiang-Ching
Kooperberg, Charles
Silveira, Angela
Starr, John M.
Strauch, Konstantin
Strawbridge, Rona J.
Wright, Alan F.
McKnight, Barbara
Franco, Oscar H.
Zakai, Neil
Mathias, Rasika A.
Psaty, Bruce M.
Ridker, Paul M.
Tofler, Geoffrey H.
Völker, Uwe
Watkins, Hugh
Fornage, Myriam
Hamsten, Anders
Deary, Ian J.
Boerwinkle, Eric
Koenig, Wolfgang
Rotter, Jerome I.
Hayward, Caroline
Dehghan, Abbas
Reiner, Alex P.
O'Donnell, Christopher J.
Smith, Nicholas L.
Title Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF
Journal name Blood   Check publisher's open access policy
ISSN 1528-0020
0006-4971
Publication date 2015-09-10
Sub-type Article (original research)
DOI 10.1182/blood-2015-02-624551
Open Access Status Not Open Access
Volume 126
Issue 11
Start page e19
End page e29
Total pages 11
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Language eng
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.
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID ETM/55
CZB/4/505
R01 HL120393
P30 CA015704
R01 HL059367
UL1 TR000124
MR/K026992/1
R01 HL105756
P30 DK063491
MC_PC_U127561128
UM1 CA182913
S10 OD020069
G0700704
BB/F019394/1
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2016 Collection
 
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