Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

John D. Eicher; Nathalie Chami; Tim Kacprowski; Akihiro Nomura; Ming Huei Chen; Lisa R. Yanek; Salman M. Tajuddin; Ursula M. Schick; Andrew J. Slater; Nathan Pankratz; Linda Polfus; Claudia Schurmann; Ayush Giri; Jennifer A. Brody; Leslie A. Lange; Ani Manichaikul; W. David Hill; Raha Pazoki; Paul Elliot; Evangelos Evangelou; Ioanna Tzoulaki; He Gao; Anne Claire Vergnaud; Rasika A. Mathias; Diane M. Becker; Lewis C. Becker; Amber Burt; David R. Crosslin; Leo Pekka Lyytikäinen; Kjell Nikus; Jussi Hernesniemi; Mika Kähönen; Emma Raitoharju; Nina Mononen; Olli T. Raitakari; Terho Lehtimäki; Mary Cushman; Neil A. Zakai; Deborah A. Nickerson; Laura M. Raffield; Rakale Quarells; Cristen J. Willer; Gina M. Peloso; Goncalo R. Abecasis; Dajiang J. Liu; Panos Deloukas; Nilesh J. Samani; Heribert Schunkert; Jeanette Erdmann; Myriam Fornage; Melissa Richard; Jean Claude Tardif; John D. Rioux; Marie Pierre Dube; Simon de Denus; Yingchang Lu; Erwin P. Bottinger; Ruth J.F. Loos; Albert Vernon Smith; Tamara B. Harris; Lenore J. Launer; Vilmundur Gudnason; Digna R. Velez Edwards; Eric S. Torstenson; Yongmei Liu; Russell P. Tracy; Jerome I. Rotter; Stephen S. Rich; Heather M. Highland; Eric Boerwinkle; Jin Li; Ethan Lange; James G. Wilson; Evelin Mihailov; Reedik Mägi; Joel Hirschhorn; Andres Metspalu; Tõnu Esko; Caterina Vacchi-Suzzi; Mike A. Nalls; Alan B. Zonderman; Michele K. Evans; Gunnar Engström; Marju Orho-Melander; Olle Melander; Michelle L. O'Donoghue; Dawn M. Waterworth; Lars Wallentin; Harvey D. White; James S. Floyd; Traci M. Bartz; Kenneth M. Rice; Bruce M. Psaty; J. M. Starr; David C.M. Liewald; Caroline Hayward; Ian J. Deary; Andreas Greinacher; Uwe Völker; Thomas Thiele; Henry Völzke; Frank J.A. van Rooij; André G. Uitterlinden; Oscar H. Franco; Abbas Dehghan; Todd L. Edwards; Santhi K. Ganesh; Sekar Kathiresan; Nauder Faraday; Paul L. Auer; Alex P. Reiner; Guillaume Lettre; Andrew D. Johnson

doi:10.1016/j.ajhg.2016.05.005

Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

John D. Eicher, Nathalie Chami, Tim Kacprowski, Akihiro Nomura, Ming Huei Chen, Lisa R. Yanek, Salman M. Tajuddin, Ursula M. Schick, Andrew J. Slater, Nathan Pankratz, Linda Polfus, Claudia Schurmann, Ayush Giri, Jennifer A. Brody, Leslie A. Lange, Ani Manichaikul, W. David Hill, Raha Pazoki, Paul Elliot, Evangelos EvangelouIoanna Tzoulaki, He Gao, Anne Claire Vergnaud, Rasika A. Mathias, Diane M. Becker, Lewis C. Becker, Amber Burt, David R. Crosslin, Leo Pekka Lyytikäinen, Kjell Nikus, Jussi Hernesniemi, Mika Kähönen, Emma Raitoharju, Nina Mononen, Olli T. Raitakari, Terho Lehtimäki, Mary Cushman, Neil A. Zakai, Deborah A. Nickerson, Laura M. Raffield, Rakale Quarells, Cristen J. Willer, Gina M. Peloso, Goncalo R. Abecasis, Dajiang J. Liu, Panos Deloukas, Nilesh J. Samani, Heribert Schunkert, Jeanette Erdmann, Myriam Fornage, Melissa Richard, Jean Claude Tardif, John D. Rioux, Marie Pierre Dube, Simon de Denus, Yingchang Lu, Erwin P. Bottinger, Ruth J.F. Loos, Albert Vernon Smith, Tamara B. Harris, Lenore J. Launer, Vilmundur Gudnason, Digna R. Velez Edwards, Eric S. Torstenson, Yongmei Liu, Russell P. Tracy, Jerome I. Rotter, Stephen S. Rich, Heather M. Highland, Eric Boerwinkle, Jin Li, Ethan Lange, James G. Wilson, Evelin Mihailov, Reedik Mägi, Joel Hirschhorn, Andres Metspalu, Tõnu Esko, Caterina Vacchi-Suzzi, Mike A. Nalls, Alan B. Zonderman, Michele K. Evans, Gunnar Engström, Marju Orho-Melander, Olle Melander, Michelle L. O'Donoghue, Dawn M. Waterworth, Lars Wallentin, Harvey D. White, James S. Floyd, Traci M. Bartz, Kenneth M. Rice, Bruce M. Psaty, J. M. Starr, David C.M. Liewald, Caroline Hayward, Ian J. Deary, Andreas Greinacher, Uwe Völker, Thomas Thiele, Henry Völzke, Frank J.A. van Rooij, André G. Uitterlinden, Oscar H. Franco, Abbas Dehghan, Todd L. Edwards, Santhi K. Ganesh, Sekar Kathiresan, Nauder Faraday, Paul L. Auer, Alex P. Reiner, Guillaume Lettre, Andrew D. Johnson

School of Medicine

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

48 Scopus citations

Abstract

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets’ important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

Original language	English (US)
Pages (from-to)	40-55
Number of pages	16
Journal	American journal of human genetics
Volume	99
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2016.05.005
State	Published - Jul 7 2016

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Eicher, J. D., Chami, N., Kacprowski, T., Nomura, A., Chen, M. H., Yanek, L. R., Tajuddin, S. M., Schick, U. M., Slater, A. J., Pankratz, N., Polfus, L., Schurmann, C., Giri, A., Brody, J. A., Lange, L. A., Manichaikul, A., Hill, W. D., Pazoki, R., Elliot, P., ... Johnson, A. D. (2016). Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. American journal of human genetics, 99(1), 40-55. https://doi.org/10.1016/j.ajhg.2016.05.005

Eicher, JD, Chami, N, Kacprowski, T, Nomura, A, Chen, MH, Yanek, LR, Tajuddin, SM, Schick, UM, Slater, AJ, Pankratz, N, Polfus, L, Schurmann, C, Giri, A, Brody, JA, Lange, LA, Manichaikul, A, Hill, WD, Pazoki, R, Elliot, P, Evangelou, E, Tzoulaki, I, Gao, H, Vergnaud, AC, Mathias, RA, Becker, DM, Becker, LC, Burt, A, Crosslin, DR, Lyytikäinen, LP, Nikus, K, Hernesniemi, J, Kähönen, M, Raitoharju, E, Mononen, N, Raitakari, OT, Lehtimäki, T, Cushman, M, Zakai, NA, Nickerson, DA, Raffield, LM, Quarells, R, Willer, CJ, Peloso, GM, Abecasis, GR, Liu, DJ, Deloukas, P, Samani, NJ, Schunkert, H, Erdmann, J, Fornage, M, Richard, M, Tardif, JC, Rioux, JD, Dube, MP, de Denus, S, Lu, Y, Bottinger, EP, Loos, RJF, Smith, AV, Harris, TB, Launer, LJ, Gudnason, V, Velez Edwards, DR, Torstenson, ES, Liu, Y, Tracy, RP, Rotter, JI, Rich, SS, Highland, HM, Boerwinkle, E, Li, J, Lange, E, Wilson, JG, Mihailov, E, Mägi, R, Hirschhorn, J, Metspalu, A, Esko, T, Vacchi-Suzzi, C, Nalls, MA, Zonderman, AB, Evans, MK, Engström, G, Orho-Melander, M, Melander, O, O'Donoghue, ML, Waterworth, DM, Wallentin, L, White, HD, Floyd, JS, Bartz, TM, Rice, KM, Psaty, BM, Starr, JM, Liewald, DCM, Hayward, C, Deary, IJ, Greinacher, A, Völker, U, Thiele, T, Völzke, H, van Rooij, FJA, Uitterlinden, AG, Franco, OH, Dehghan, A, Edwards, TL, Ganesh, SK, Kathiresan, S, Faraday, N, Auer, PL, Reiner, AP, Lettre, G & Johnson, AD 2016, 'Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals', American journal of human genetics, vol. 99, no. 1, pp. 40-55. https://doi.org/10.1016/j.ajhg.2016.05.005

@article{e8006e83f8444163bd8aa2b7449d0aa8,

title = "Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals",

abstract = "Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets{\textquoteright} important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.",

author = "Eicher, {John D.} and Nathalie Chami and Tim Kacprowski and Akihiro Nomura and Chen, {Ming Huei} and Yanek, {Lisa R.} and Tajuddin, {Salman M.} and Schick, {Ursula M.} and Slater, {Andrew J.} and Nathan Pankratz and Linda Polfus and Claudia Schurmann and Ayush Giri and Brody, {Jennifer A.} and Lange, {Leslie A.} and Ani Manichaikul and Hill, {W. David} and Raha Pazoki and Paul Elliot and Evangelos Evangelou and Ioanna Tzoulaki and He Gao and Vergnaud, {Anne Claire} and Mathias, {Rasika A.} and Becker, {Diane M.} and Becker, {Lewis C.} and Amber Burt and Crosslin, {David R.} and Lyytik{\"a}inen, {Leo Pekka} and Kjell Nikus and Jussi Hernesniemi and Mika K{\"a}h{\"o}nen and Emma Raitoharju and Nina Mononen and Raitakari, {Olli T.} and Terho Lehtim{\"a}ki and Mary Cushman and Zakai, {Neil A.} and Nickerson, {Deborah A.} and Raffield, {Laura M.} and Rakale Quarells and Willer, {Cristen J.} and Peloso, {Gina M.} and Abecasis, {Goncalo R.} and Liu, {Dajiang J.} and Panos Deloukas and Samani, {Nilesh J.} and Heribert Schunkert and Jeanette Erdmann and Myriam Fornage and Melissa Richard and Tardif, {Jean Claude} and Rioux, {John D.} and Dube, {Marie Pierre} and {de Denus}, Simon and Yingchang Lu and Bottinger, {Erwin P.} and Loos, {Ruth J.F.} and Smith, {Albert Vernon} and Harris, {Tamara B.} and Launer, {Lenore J.} and Vilmundur Gudnason and {Velez Edwards}, {Digna R.} and Torstenson, {Eric S.} and Yongmei Liu and Tracy, {Russell P.} and Rotter, {Jerome I.} and Rich, {Stephen S.} and Highland, {Heather M.} and Eric Boerwinkle and Jin Li and Ethan Lange and Wilson, {James G.} and Evelin Mihailov and Reedik M{\"a}gi and Joel Hirschhorn and Andres Metspalu and T{\~o}nu Esko and Caterina Vacchi-Suzzi and Nalls, {Mike A.} and Zonderman, {Alan B.} and Evans, {Michele K.} and Gunnar Engstr{\"o}m and Marju Orho-Melander and Olle Melander and O'Donoghue, {Michelle L.} and Waterworth, {Dawn M.} and Lars Wallentin and White, {Harvey D.} and Floyd, {James S.} and Bartz, {Traci M.} and Rice, {Kenneth M.} and Psaty, {Bruce M.} and Starr, {J. M.} and Liewald, {David C.M.} and Caroline Hayward and Deary, {Ian J.} and Andreas Greinacher and Uwe V{\"o}lker and Thomas Thiele and Henry V{\"o}lzke and {van Rooij}, {Frank J.A.} and Uitterlinden, {Andr{\'e} G.} and Franco, {Oscar H.} and Abbas Dehghan and Edwards, {Todd L.} and Ganesh, {Santhi K.} and Sekar Kathiresan and Nauder Faraday and Auer, {Paul L.} and Reiner, {Alex P.} and Guillaume Lettre and Johnson, {Andrew D.}",

note = "Publisher Copyright: {\textcopyright} 2016",

year = "2016",

month = jul,

day = "7",

doi = "10.1016/j.ajhg.2016.05.005",

language = "English (US)",

volume = "99",

pages = "40--55",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

AU - Eicher, John D.

AU - Chami, Nathalie

AU - Kacprowski, Tim

AU - Nomura, Akihiro

AU - Chen, Ming Huei

AU - Yanek, Lisa R.

AU - Tajuddin, Salman M.

AU - Schick, Ursula M.

AU - Slater, Andrew J.

AU - Pankratz, Nathan

AU - Polfus, Linda

AU - Schurmann, Claudia

AU - Giri, Ayush

AU - Brody, Jennifer A.

AU - Lange, Leslie A.

AU - Manichaikul, Ani

AU - Hill, W. David

AU - Pazoki, Raha

AU - Elliot, Paul

AU - Evangelou, Evangelos

AU - Tzoulaki, Ioanna

AU - Gao, He

AU - Vergnaud, Anne Claire

AU - Mathias, Rasika A.

AU - Becker, Diane M.

AU - Becker, Lewis C.

AU - Burt, Amber

AU - Crosslin, David R.

AU - Lyytikäinen, Leo Pekka

AU - Nikus, Kjell

AU - Hernesniemi, Jussi

AU - Kähönen, Mika

AU - Raitoharju, Emma

AU - Mononen, Nina

AU - Raitakari, Olli T.

AU - Lehtimäki, Terho

AU - Cushman, Mary

AU - Zakai, Neil A.

AU - Nickerson, Deborah A.

AU - Raffield, Laura M.

AU - Quarells, Rakale

AU - Willer, Cristen J.

AU - Peloso, Gina M.

AU - Abecasis, Goncalo R.

AU - Liu, Dajiang J.

AU - Deloukas, Panos

AU - Samani, Nilesh J.

AU - Schunkert, Heribert

AU - Erdmann, Jeanette

AU - Fornage, Myriam

AU - Richard, Melissa

AU - Tardif, Jean Claude

AU - Rioux, John D.

AU - Dube, Marie Pierre

AU - de Denus, Simon

AU - Lu, Yingchang

AU - Bottinger, Erwin P.

AU - Loos, Ruth J.F.

AU - Smith, Albert Vernon

AU - Harris, Tamara B.

AU - Launer, Lenore J.

AU - Gudnason, Vilmundur

AU - Velez Edwards, Digna R.

AU - Torstenson, Eric S.

AU - Liu, Yongmei

AU - Tracy, Russell P.

AU - Rotter, Jerome I.

AU - Rich, Stephen S.

AU - Highland, Heather M.

AU - Boerwinkle, Eric

AU - Li, Jin

AU - Lange, Ethan

AU - Wilson, James G.

AU - Mihailov, Evelin

AU - Mägi, Reedik

AU - Hirschhorn, Joel

AU - Metspalu, Andres

AU - Esko, Tõnu

AU - Vacchi-Suzzi, Caterina

AU - Nalls, Mike A.

AU - Zonderman, Alan B.

AU - Evans, Michele K.

AU - Engström, Gunnar

AU - Orho-Melander, Marju

AU - Melander, Olle

AU - O'Donoghue, Michelle L.

AU - Waterworth, Dawn M.

AU - Wallentin, Lars

AU - White, Harvey D.

AU - Floyd, James S.

AU - Bartz, Traci M.

AU - Rice, Kenneth M.

AU - Psaty, Bruce M.

AU - Starr, J. M.

AU - Liewald, David C.M.

AU - Hayward, Caroline

AU - Deary, Ian J.

AU - Greinacher, Andreas

AU - Völker, Uwe

AU - Thiele, Thomas

AU - Völzke, Henry

AU - van Rooij, Frank J.A.

AU - Uitterlinden, André G.

AU - Franco, Oscar H.

AU - Dehghan, Abbas

AU - Edwards, Todd L.

AU - Ganesh, Santhi K.

AU - Kathiresan, Sekar

AU - Faraday, Nauder

AU - Auer, Paul L.

AU - Reiner, Alex P.

AU - Lettre, Guillaume

AU - Johnson, Andrew D.

PY - 2016/7/7

Y1 - 2016/7/7

N2 - Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets’ important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

AB - Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets’ important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

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UR - http://www.scopus.com/inward/citedby.url?scp=84989952555&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2016.05.005

DO - 10.1016/j.ajhg.2016.05.005

M3 - Article

C2 - 27346686

AN - SCOPUS:84989952555

SN - 0002-9297

VL - 99

SP - 40

EP - 55

JO - American journal of human genetics

JF - American journal of human genetics

IS - 1

ER -

Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

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