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 & 93 others 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 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

Research output: Contribution to journalArticle

30 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)40-55
Number of pages16
JournalAmerican Journal of Human Genetics
Volume99
Issue number1
DOIs
StatePublished - Jul 7 2016

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Mean Platelet Volume
Platelet Count
Meta-Analysis
Blood Platelets
Blood Cells
Blood Cell Count
Primary Prevention
Secondary Prevention
Hemostasis
Gene Frequency
Thrombosis
Maintenance
Lipids

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Eicher, J. D., Chami, N., Kacprowski, T., Nomura, A., Chen, M. H., Yanek, L. R., ... 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, John D. ; Chami, Nathalie ; Kacprowski, Tim ; Nomura, Akihiro ; Chen, Ming Huei ; Yanek, Lisa R. ; Tajuddin, Salman M. ; Schick, Ursula M. ; Slater, Andrew J. ; Pankratz, Nathan ; Polfus, Linda ; Schurmann, Claudia ; Giri, Ayush ; Brody, Jennifer A. ; Lange, Leslie A. ; Manichaikul, Ani ; Hill, W. David ; Pazoki, Raha ; Elliot, Paul ; Evangelou, Evangelos ; Tzoulaki, Ioanna ; Gao, He ; Vergnaud, Anne Claire ; Mathias, Rasika A. ; Becker, Diane M. ; Becker, Lewis C. ; Burt, Amber ; Crosslin, David R. ; Lyytikäinen, Leo Pekka ; Nikus, Kjell ; Hernesniemi, Jussi ; Kähönen, Mika ; Raitoharju, Emma ; Mononen, Nina ; Raitakari, Olli T. ; Lehtimäki, Terho ; Cushman, Mary ; Zakai, Neil A. ; Nickerson, Deborah A. ; Raffield, Laura M. ; Quarells, Rakale ; Willer, Cristen J. ; Peloso, Gina M. ; Abecasis, Goncalo R. ; Liu, Dajiang ; Deloukas, Panos ; Samani, Nilesh J. ; Schunkert, Heribert ; Erdmann, Jeanette ; Fornage, Myriam ; Richard, Melissa ; Tardif, Jean Claude ; Rioux, John D. ; Dube, Marie Pierre ; de Denus, Simon ; Lu, Yingchang ; Bottinger, Erwin P. ; Loos, Ruth J.F. ; Smith, Albert Vernon ; Harris, Tamara B. ; Launer, Lenore J. ; Gudnason, Vilmundur ; Velez Edwards, Digna R. ; Torstenson, Eric S. ; Liu, Yongmei ; Tracy, Russell P. ; Rotter, Jerome I. ; Rich, Stephen S. ; Highland, Heather M. ; Boerwinkle, Eric ; Li, Jin ; Lange, Ethan ; Wilson, James G. ; Mihailov, Evelin ; Mägi, Reedik ; Hirschhorn, Joel ; Metspalu, Andres ; Esko, Tõnu ; Vacchi-Suzzi, Caterina ; Nalls, Mike A. ; Zonderman, Alan B. ; Evans, Michele K. ; Engström, Gunnar ; Orho-Melander, Marju ; Melander, Olle ; O'Donoghue, Michelle L. ; Waterworth, Dawn M. ; Wallentin, Lars ; White, Harvey D. ; Floyd, James S. ; Bartz, Traci M. ; Rice, Kenneth M. ; Psaty, Bruce M. ; Starr, J. M. ; Liewald, David C.M. ; Hayward, Caroline ; Deary, Ian J. ; Greinacher, Andreas ; Völker, Uwe ; Thiele, Thomas ; Völzke, Henry ; van Rooij, Frank J.A. ; Uitterlinden, André G. ; Franco, Oscar H. ; Dehghan, Abbas ; Edwards, Todd L. ; Ganesh, Santhi K. ; Kathiresan, Sekar ; Faraday, Nauder ; Auer, Paul L. ; Reiner, Alex P. ; Lettre, Guillaume ; Johnson, Andrew D. / Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 1. pp. 40-55.
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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.",
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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, D, 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

Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. / Eicher, John D.; Chami, Nathalie; Kacprowski, Tim; Nomura, Akihiro; Chen, Ming Huei; Yanek, Lisa R.; Tajuddin, Salman M.; Schick, Ursula M.; Slater, Andrew J.; Pankratz, Nathan; Polfus, Linda; Schurmann, Claudia; Giri, Ayush; Brody, Jennifer A.; Lange, Leslie A.; Manichaikul, Ani; Hill, W. David; Pazoki, Raha; Elliot, Paul; Evangelou, Evangelos; Tzoulaki, Ioanna; Gao, He; Vergnaud, Anne Claire; Mathias, Rasika A.; Becker, Diane M.; Becker, Lewis C.; Burt, Amber; Crosslin, David R.; Lyytikäinen, Leo Pekka; Nikus, Kjell; Hernesniemi, Jussi; Kähönen, Mika; Raitoharju, Emma; Mononen, Nina; Raitakari, Olli T.; Lehtimäki, Terho; Cushman, Mary; Zakai, Neil A.; Nickerson, Deborah A.; Raffield, Laura M.; Quarells, Rakale; Willer, Cristen J.; Peloso, Gina M.; Abecasis, Goncalo R.; Liu, Dajiang; Deloukas, Panos; Samani, Nilesh J.; Schunkert, Heribert; Erdmann, Jeanette; Fornage, Myriam; Richard, Melissa; Tardif, Jean Claude; Rioux, John D.; Dube, Marie Pierre; de Denus, Simon; Lu, Yingchang; Bottinger, Erwin P.; Loos, Ruth J.F.; Smith, Albert Vernon; Harris, Tamara B.; Launer, Lenore J.; Gudnason, Vilmundur; Velez Edwards, Digna R.; Torstenson, Eric S.; Liu, Yongmei; Tracy, Russell P.; Rotter, Jerome I.; Rich, Stephen S.; Highland, Heather M.; Boerwinkle, Eric; Li, Jin; Lange, Ethan; Wilson, James G.; Mihailov, Evelin; Mägi, Reedik; Hirschhorn, Joel; Metspalu, Andres; Esko, Tõnu; Vacchi-Suzzi, Caterina; Nalls, Mike A.; Zonderman, Alan B.; Evans, Michele K.; Engström, Gunnar; Orho-Melander, Marju; Melander, Olle; O'Donoghue, Michelle L.; Waterworth, Dawn M.; Wallentin, Lars; White, Harvey D.; Floyd, James S.; Bartz, Traci M.; Rice, Kenneth M.; Psaty, Bruce M.; Starr, J. M.; Liewald, David C.M.; Hayward, Caroline; Deary, Ian J.; Greinacher, Andreas; Völker, Uwe; Thiele, Thomas; Völzke, Henry; van Rooij, Frank J.A.; Uitterlinden, André G.; Franco, Oscar H.; Dehghan, Abbas; Edwards, Todd L.; Ganesh, Santhi K.; Kathiresan, Sekar; Faraday, Nauder; Auer, Paul L.; Reiner, Alex P.; Lettre, Guillaume; Johnson, Andrew D.

In: American Journal of Human Genetics, Vol. 99, No. 1, 07.07.2016, p. 40-55.

Research output: Contribution to journalArticle

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

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

VL - 99

SP - 40

EP - 55

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

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