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

JE Huffman; PS Vries; AC Morrison; M Sabater-Lleal; T Kacprowski; PL Auer; JA Brody; DI Chasman; MH Chen; XQ Guo; LA Lin; RE Marioni; M Muller-Nurasyid; LR Yanek; N Pankratz; ML Grove; Moniek de Maat; M Cushman; KL Wiggins; LH Qi; B Sennblad; SE Harris; O Polasek; H Riess; Fernando Rivadeneira; LM Rose; A Goel; KD Taylor; A Teumer; André Uitterlinden; D Vaidya; J Yao; WH Tang; D Levy; M Waldenberger; DM Becker; AR Folsom; F Giulianini; A Greinacher; Bert Hofman; CC Huang; C Kooperberg; A Silveira; JM Starr; K Strauch; RJ Strawbridge; AF Wright; B McKnight; OH Franco Duran; N Zakai; RA Mathias; BM Psaty; PM Ridker; GH Tofler; U Volker; H Watkins; M Fornage; A Hamsten; IJ Deary; E Boerwinkle; W Koenig; JI Rotter; C Hayward; Abbas Dehghan; AP Reiner; CJ O'Donnell; NL 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

JE Huffman, PS Vries, AC Morrison, M Sabater-Lleal, T Kacprowski, PL Auer, JA Brody, DI Chasman, MH Chen, XQ Guo, LA Lin, RE Marioni, M Muller-Nurasyid, LR Yanek, N Pankratz, ML Grove, Moniek de Maat, M Cushman, KL Wiggins, LH QiB Sennblad, SE Harris, O Polasek, H Riess, Fernando Rivadeneira, LM Rose, A Goel, KD Taylor, A Teumer, André Uitterlinden, D Vaidya, J Yao, WH Tang, D Levy, M Waldenberger, DM Becker, AR Folsom, F Giulianini, A Greinacher, Bert Hofman, CC Huang, C Kooperberg, A Silveira, JM Starr, K Strauch, RJ Strawbridge, AF Wright, B McKnight, OH Franco Duran, N Zakai, RA Mathias, BM Psaty, PM Ridker, GH Tofler, U Volker, H Watkins, M Fornage, A Hamsten, IJ Deary, E Boerwinkle, W Koenig, JI Rotter, C Hayward, Abbas Dehghan, AP Reiner, CJ O'Donnell, NL Smith

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

41 Citations (Scopus)

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.

Original language	Undefined/Unknown
Pages (from-to)	E19-E29
Journal	Blood
Volume	126
Issue number	11
DOIs	https://doi.org/10.1182/blood-2015-02-624551
Publication status	Published - 2015

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10.1182/blood-2015-02-624551

http://hdl.handle.net/1765/91248

Cite this

Huffman, JE., Vries, PS., Morrison, AC., Sabater-Lleal, M., Kacprowski, T., Auer, PL., Brody, JA., Chasman, DI., Chen, MH., Guo, XQ., Lin, LA., Marioni, RE., Muller-Nurasyid, M., Yanek, LR., Pankratz, N., Grove, ML., de Maat, M., Cushman, M., Wiggins, KL., ... Smith, NL. (2015). Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. Blood, 126(11), E19-E29. https://doi.org/10.1182/blood-2015-02-624551

@article{9379b85778114550b00df6c8226b0a55,

title = "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) 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.",

author = "JE Huffman and PS Vries and AC Morrison and M Sabater-Lleal and T Kacprowski and PL Auer and JA Brody and DI Chasman and MH Chen and XQ Guo and LA Lin and RE Marioni and M Muller-Nurasyid and LR Yanek and N Pankratz and ML Grove and {de Maat}, Moniek and M Cushman and KL Wiggins and LH Qi and B Sennblad and SE Harris and O Polasek and H Riess and Fernando Rivadeneira and LM Rose and A Goel and KD Taylor and A Teumer and Andr{\'e} Uitterlinden and D Vaidya and J Yao and WH Tang and D Levy and M Waldenberger and DM Becker and AR Folsom and F Giulianini and A Greinacher and Bert Hofman and CC Huang and C Kooperberg and A Silveira and JM Starr and K Strauch and RJ Strawbridge and AF Wright and B McKnight and {Franco Duran}, OH and N Zakai and RA Mathias and BM Psaty and PM Ridker and GH Tofler and U Volker and H Watkins and M Fornage and A Hamsten and IJ Deary and E Boerwinkle and W Koenig and JI Rotter and C Hayward and Abbas Dehghan and AP Reiner and CJ O'Donnell and NL Smith",

year = "2015",

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

language = "Undefined/Unknown",

volume = "126",

pages = "E19--E29",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "11",

}

Huffman, JE, Vries, PS, Morrison, AC, Sabater-Lleal, M, Kacprowski, T, Auer, PL, Brody, JA, Chasman, DI, Chen, MH, Guo, XQ, Lin, LA, Marioni, RE, Muller-Nurasyid, M, Yanek, LR, Pankratz, N, Grove, ML, de Maat, M, Cushman, M, Wiggins, KL, Qi, LH, Sennblad, B, Harris, SE, Polasek, O, Riess, H, Rivadeneira, F, Rose, LM, Goel, A, Taylor, KD, Teumer, A, Uitterlinden, A, Vaidya, D, Yao, J, Tang, WH, Levy, D, Waldenberger, M, Becker, DM, Folsom, AR, Giulianini, F, Greinacher, A, Hofman, B, Huang, CC, Kooperberg, C, Silveira, A, Starr, JM, Strauch, K, Strawbridge, RJ, Wright, AF, McKnight, B, Franco Duran, OH, Zakai, N, Mathias, RA, Psaty, BM, Ridker, PM, Tofler, GH, Volker, 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 2015, 'Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF', Blood, vol. 126, no. 11, pp. E19-E29. 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, JE

AU - Vries, PS

AU - Morrison, AC

AU - Sabater-Lleal, M

AU - Kacprowski, T

AU - Auer, PL

AU - Brody, JA

AU - Chasman, DI

AU - Chen, MH

AU - Guo, XQ

AU - Lin, LA

AU - Marioni, RE

AU - Muller-Nurasyid, M

AU - Yanek, LR

AU - Pankratz, N

AU - Grove, ML

AU - de Maat, Moniek

AU - Cushman, M

AU - Wiggins, KL

AU - Qi, LH

AU - Sennblad, B

AU - Harris, SE

AU - Polasek, O

AU - Riess, H

AU - Rivadeneira, Fernando

AU - Rose, LM

AU - Goel, A

AU - Taylor, KD

AU - Teumer, A

AU - Uitterlinden, André

AU - Vaidya, D

AU - Yao, J

AU - Tang, WH

AU - Levy, D

AU - Waldenberger, M

AU - Becker, DM

AU - Folsom, AR

AU - Giulianini, F

AU - Greinacher, A

AU - Hofman, Bert

AU - Huang, CC

AU - Kooperberg, C

AU - Silveira, A

AU - Starr, JM

AU - Strauch, K

AU - Strawbridge, RJ

AU - Wright, AF

AU - McKnight, B

AU - Franco Duran, OH

AU - Zakai, N

AU - Mathias, RA

AU - Psaty, BM

AU - Ridker, PM

AU - Tofler, GH

AU - Volker, U

AU - Watkins, H

AU - Fornage, M

AU - Hamsten, A

AU - Deary, IJ

AU - Boerwinkle, E

AU - Koenig, W

AU - Rotter, JI

AU - Hayward, C

AU - Dehghan, Abbas

AU - Reiner, AP

AU - O'Donnell, CJ

AU - Smith, NL

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1182/blood-2015-02-624551

DO - 10.1182/blood-2015-02-624551

M3 - Article

SN - 0006-4971

VL - 126

SP - E19-E29

JO - Blood

JF - Blood

IS - 11

ER -