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

Global Lipids Genetics Consortium; 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

doi:10.1016/j.ajhg.2016.05.005

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

Global Lipids Genetics Consortium
, 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

NHLBI's Framingham Heart Study
Harvard University
Johns Hopkins University
The National Institute of Environmental Health Sciences
University of Minnesota School of Public Health
Baylor College of Medicine
University of North Carolina
University College London
University of Washington, Seattle
University of Tampere School of Medicine
University of Turku
University of Vermont College of Medicine
Morehouse School of Medicine
University of Michigan
Pennsylvania State University
Queen Mary University of London
University of Leicester
Université de Montréal
Universität Greifswald
National Institute on Aging
Charles Bronfman Institute for Personalized Medicine
Vanderbilt University
University of Virginia
University of Edinburgh
Erasmus Medical College

77 Zitate (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.

Originalsprache	Englisch
Zeitschrift	American Journal of Human Genetics
Jahrgang	99
Ausgabenummer	1
Seiten (von - bis)	40-55
Seitenumfang	16
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2016.05.005
Publikationsstatus	Veröffentlicht - 07.07.2016

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10.1016/j.ajhg.2016.05.005

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Global Lipids Genetics Consortium, 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., ... Fornage, M. (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

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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' 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 = "\{Global Lipids Genetics Consortium\} and Eicher, \{John D\} and Nathalie Chami and Tim Kacprowski and Akihiro Nomura and Ming-Huei Chen 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 Anne-Claire Vergnaud and Mathias, \{Rasika A\} and Becker, \{Diane M\} and Becker, \{Lewis C\} and Amber Burt and Crosslin, \{David R\} and Leo-Pekka Lyytik{\"a}inen 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",

note = "Published by Elsevier Inc.",

year = "2016",

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day = "7",

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

language = "English",

volume = "99",

pages = "40--55",

journal = "American Journal of Human Genetics",

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Global Lipids Genetics Consortium, Eicher, JD, Chami, N, Kacprowski, T, Nomura, A, Chen, M-H, 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, A-C, Mathias, RA, Becker, DM, Becker, LC, Burt, A, Crosslin, DR, Lyytikäinen, L-P, 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 2016, 'Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals', American Journal of Human Genetics, Jg. 99, Nr. 1, S. 40-55. https://doi.org/10.1016/j.ajhg.2016.05.005

TY - JOUR

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

AU - Global Lipids Genetics Consortium

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

N1 - Published by Elsevier Inc.

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.

U2 - 10.1016/j.ajhg.2016.05.005

DO - 10.1016/j.ajhg.2016.05.005

M3 - Journal articles

C2 - 27346686

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

Abstract

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