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

Jennifer E. Huffman; Paul  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 Marioni; Martina muller-nurasyid; Lisa R Yanek; Nathan Pankratz; Megan L Grove; Moniek P. M. de Maat; Mary Cushman; Kerri L. Wiggins; Lihong Qi; Bengt Sennblad; Sarah Harris; Ozren Polašek; Helene Riess; Fernando Rivadeneira; Lynda M. Rose; Anuj Goel; Kent D. Taylor; Alexander Teumer; Andre 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 Voelker; Hugh Watkins; Myriam Fornage; Anders Hamsten; Ian Deary; Eric Boerwinkle; Wolfgang Koenig; Jerome I. Rotter; Caroline Hayward; Abbas Dehghan; Alex P Reiner; Christopher J. O'Donnell; Nicholas L. Smith

doi:10.1182/blood-2015-02-624551

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

Jennifer E. Huffman, Paul 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 Marioni, Martina muller-nurasyid, Lisa R Yanek, Nathan Pankratz, Megan L Grove, Moniek P. M. de Maat, Mary Cushman, Kerri L. Wiggins, Lihong QiBengt Sennblad, Sarah Harris, Ozren Polašek, Helene Riess, Fernando Rivadeneira, Lynda M. Rose, Anuj Goel, Kent D. Taylor, Alexander Teumer, Andre 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 Voelker, Hugh Watkins, Myriam Fornage, Anders Hamsten, Ian Deary, Eric Boerwinkle, Wolfgang Koenig, Jerome I. Rotter, Caroline Hayward, Abbas Dehghan, Alex P Reiner, Christopher J. O'Donnell, Nicholas L. Smith

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Fibrinogen, coagulation factor VII (FVII), 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 variation 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 identify 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 to understanding individual variation in hemostasis pathways.

Original language	English
Journal	Blood
DOIs	https://doi.org/10.1182/blood-2015-02-624551
Publication status	Published - 23 Jun 2015

Access to Document

10.1182/blood-2015-02-624551

HemostatisEC_Draft_v16
This is the final author's manuscript as accepted for publication
Accepted author manuscript, 264 KB

http://www.bloodjournal.org/content/early/2015/06/22/blood-2015-02-624551?sso-checked=true

Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.
Maclullich, A.
1/09/13 → 31/08/19
Project: Research
RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
Project: Research
Disconnected Mind [Phase 2]
Wardlaw, J.
UK-based charities
1/01/11 → 31/03/16
Project: Research

Cite this

Huffman, J. E., de Vries, P., Morrison, A. C., Sabater-Lleal, M., Kacprowski, T., Auer, P. L., Brody, J. A., Chasman, D. I., Chen, M.-H., Guo, X., Lin, L.-A., Marioni, R., muller-nurasyid, M., Yanek, L. R., Pankratz, N., Grove, M. L., de Maat, M. P. M., Cushman, M., Wiggins, K. L., ... Smith, N. L. (2015). Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. Blood. https://doi.org/10.1182/blood-2015-02-624551

@article{85f7cec49e484592869786af643e71a4,

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

abstract = "Fibrinogen, coagulation factor VII (FVII), 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 variation 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 identify 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 to understanding individual variation in hemostasis pathways.",

author = "Huffman, {Jennifer E.} and {de Vries}, Paul and Morrison, {Alanna C.} and Maria Sabater-Lleal and Tim Kacprowski and Auer, {Paul L} and Brody, {Jennifer A} and Chasman, {Daniel I.} and Ming-Huei Chen and Xiuqing Guo and Li-An Lin and Riccardo Marioni and Martina muller-nurasyid and Yanek, {Lisa R} and Nathan Pankratz and Grove, {Megan L} and {de Maat}, {Moniek P. M.} and Mary Cushman and Wiggins, {Kerri L.} and Lihong Qi and Bengt Sennblad and Sarah Harris and Ozren Pola{\v s}ek and Helene Riess and Fernando Rivadeneira and Rose, {Lynda M.} and Anuj Goel and Taylor, {Kent D.} and Alexander Teumer and Uitterlinden, {Andre G} and dhananjay Vaidya and Jie Yao and Weihong Tang and Daniel Levy and Melanie Waldenberger and Becker, {Diane M} and Folsom, {Aaron R.} and Franco Giulianini and Andreas Greinacher and Albert Hofman and Chiang-Ching Huang and Charles Kooperberg and Angela Silveira and Starr, {John M.} and Konstantin Strauch and Strawbridge, {Rona J.} and Wright, {Alan F.} and Barbara McKnight and Franco, {Oscar H} and Neil Zakai and Mathias, {Rasika A} and Psaty, {Bruce M.} and Ridker, {Paul M.} and Tofler, {Geoffrey H.} and Uwe Voelker and Hugh Watkins and Myriam Fornage and Anders Hamsten and Ian Deary and Eric Boerwinkle and Wolfgang Koenig and Rotter, {Jerome I.} and Caroline Hayward and Abbas Dehghan and Reiner, {Alex P} and O'Donnell, {Christopher J.} and Smith, {Nicholas L.}",

year = "2015",

month = jun,

day = "23",

doi = "10.1182/blood-2015-02-624551",

language = "English",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

}

Huffman, JE, de Vries, P, Morrison, AC, Sabater-Lleal, M, Kacprowski, T, Auer, PL, Brody, JA, Chasman, DI, Chen, M-H, Guo, X, Lin, L-A, Marioni, R, muller-nurasyid, M, Yanek, LR, Pankratz, N, Grove, ML, de Maat, MPM, Cushman, M, Wiggins, KL, Qi, L, Sennblad, B, Harris, S, Polašek, 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, Voelker, U, Watkins, H, Fornage, M, Hamsten, A, Deary, I, Boerwinkle, E, Koenig, W, Rotter, JI, Hayward, C, Dehghan, A, Reiner, AP, O'Donnell, CJ & Smith, NL 2015, 'Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF', Blood. https://doi.org/10.1182/blood-2015-02-624551

TY - JOUR

T1 - Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

AU - Huffman, Jennifer E.

AU - de Vries, Paul

AU - Morrison, Alanna C.

AU - Sabater-Lleal, Maria

AU - Kacprowski, Tim

AU - Auer, Paul L

AU - Brody, Jennifer A

AU - Chasman, Daniel I.

AU - Chen, Ming-Huei

AU - Guo, Xiuqing

AU - Lin, Li-An

AU - Marioni, Riccardo

AU - muller-nurasyid, Martina

AU - Yanek, Lisa R

AU - Pankratz, Nathan

AU - Grove, Megan L

AU - de Maat, Moniek P. M.

AU - Cushman, Mary

AU - Wiggins, Kerri L.

AU - Qi, Lihong

AU - Sennblad, Bengt

AU - Harris, Sarah

AU - Polašek, Ozren

AU - Riess, Helene

AU - Rivadeneira, Fernando

AU - Rose, Lynda M.

AU - Goel, Anuj

AU - Taylor, Kent D.

AU - Teumer, Alexander

AU - Uitterlinden, Andre G

AU - Vaidya, dhananjay

AU - Yao, Jie

AU - Tang, Weihong

AU - Levy, Daniel

AU - Waldenberger, Melanie

AU - Becker, Diane M

AU - Folsom, Aaron R.

AU - Giulianini, Franco

AU - Greinacher, Andreas

AU - Hofman, Albert

AU - Huang, Chiang-Ching

AU - Kooperberg, Charles

AU - Silveira, Angela

AU - Starr, John M.

AU - Strauch, Konstantin

AU - Strawbridge, Rona J.

AU - Wright, Alan F.

AU - McKnight, Barbara

AU - Franco, Oscar H

AU - Zakai, Neil

AU - Mathias, Rasika A

AU - Psaty, Bruce M.

AU - Ridker, Paul M.

AU - Tofler, Geoffrey H.

AU - Voelker, Uwe

AU - Watkins, Hugh

AU - Fornage, Myriam

AU - Hamsten, Anders

AU - Deary, Ian

AU - Boerwinkle, Eric

AU - Koenig, Wolfgang

AU - Rotter, Jerome I.

AU - Hayward, Caroline

AU - Dehghan, Abbas

AU - Reiner, Alex P

AU - O'Donnell, Christopher J.

AU - Smith, Nicholas L.

PY - 2015/6/23

Y1 - 2015/6/23

N2 - Fibrinogen, coagulation factor VII (FVII), 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 variation 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 identify 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 to understanding individual variation in hemostasis pathways.

AB - Fibrinogen, coagulation factor VII (FVII), 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 variation 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 identify 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 to understanding individual variation in hemostasis pathways.

U2 - 10.1182/blood-2015-02-624551

DO - 10.1182/blood-2015-02-624551

M3 - Article

SN - 0006-4971

JO - Blood

JF - Blood

ER -

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

Abstract / Description of output

Access to Document

Fingerprint

Projects

Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

Disconnected Mind [Phase 2]

Cite this