Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals
Creators: name: Hernesniemi, Jussi
name: Rotter, Jerome I.
name: Reiner, Alex P.
name: Uitterlinden, André G.
name: Abecasis, Goncalo R.
name: Velez Edwards, Digna R.
name: Schick, Ursula M.
name: Yanek, Lisa R.
name: Lettre, Guillaume
name: Zakai, Neil A.
name: Lyytikäinen, Leo-Pekka
name: Boerwinkle, Eric
name: White, Harvey D.
name: Schurmann, Claudia
name: Kacprowski, Tim
name: Bottinger, Erwin P.
name: Esko, Tõnu
name: Mononen, Nina
name: Lange, Ethan
name: Evans, Michele K.
name: Smith, Albert Vernon
name: Waterworth, Dawn M.
name: Eicher, John D.
name: Lehtimäki, Terho
name: Ganesh, Santhi K.
name: Gao, He
name: Rioux, John D.
name: Fornage, Myriam
name: Psaty, Bruce M.
name: Nickerson, Deborah A.
name: Crosslin, David R.
name: Bartz, Traci M.
name: Franco, Oscar H.
name: Erdmann, Jeanette
name: Gudnason, Vilmundur
name: Floyd, James S.
name: Becker, Diane M.
name: Mathias, Rasika A.
name: Starr, 
name: Chen, Ming-Huei
name: Edwards, Todd L.
name: Pankratz, Nathan
name: Burt, Amber
name: Vacchi-Suzzi, Caterina
name: Samani, Nilesh J.
name: Rich, Stephen S.
name: Lange, Leslie A.
name: Chami, Nathalie
name: Raitoharju, Emma
name: Orho-Melander, Marju
name: Nikus, Kjell
name: Johnson, Andrew D.
name: Nomura, Akihiro
name: Deloukas, Panos
name: Dehghan, Abbas
name: Harris, Tamara B.
name: Elliot, Paul
name: Liewald, David C.M.
name: Willer, Cristen J.
name: Tajuddin, Salman M.
name: Pazoki, Raha
name: van Rooij, Frank J.A.
name: Wallentin, Lars
name: Liu, Yongmei
name: Becker, Lewis C.
name: Lu, Yingchang
name: Völker, Uwe
name: Slater, Andrew J.
name: Evangelou, Evangelos
name: Rice, Kenneth M.
name: Launer, Lenore J.
name: Richard, Melissa
name: Schunkert, Heribert
name: Kathiresan, Sekar
name: Mägi, Reedik
name: de Denus, Simon
name: Tzoulaki, Ioanna
name: Giri, Ayush
name: Peloso, Gina M.
name: Nalls, Mike A.
name: Raffield, Laura M.
name: Liu, Dajiang J.
name: Hirschhorn, Joel
name: Melander, Olle
name: Hill, W. David
name: Metspalu, Andres
name: Loos, Ruth J.F.
name: Tardif, Jean-Claude
name: Manichaikul, Ani
name: O'Donoghue, Michelle L.
name: Greinacher, Andreas
name: Kähönen, Mika
name: Engström, Gunnar
name: Quarells, Rakale
name: Völzke, Henry
name: Deary, Ian J.
name: Torstenson, Eric S.
name: Mihailov, Evelin
name: Tracy, Russell P.
name: Dube, Marie-Pierre
name: Li, Jin
name: Cushman, Mary
name: Wilson, James G.
name: Raitakari, Olli T.
name: Highland, Heather M.
name: Vergnaud, Anne-Claire
name: Polfus, Linda
name: Zonderman, Alan B.
name: Auer, Paul L.
name: Hayward, Caroline
name: Brody, Jennifer A.
name: Thiele, Thomas
name: Faraday, Nauder
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2016

description: 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.