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

 
TitlePlatelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.
Publication TypeJournal Article
Year of Publication2016
AuthorsEicher, 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, W Hill, D, 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, Richard, M, Tardif, J-C, Rioux, JD, Dube, M-P, de Denus, S, Lu, Y, Bottinger, EP, Loos, RJF, Smith, AVernon, Harris, TB, Launer, LJ, Gudnason, V, Edwards, DRVelez, 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
Corporate AuthorsGlobal Lipids Genetics Consortium, CARDIOGRAM Exome Consortium, Myocardial Infarction Genetics Consortium
JournalAm J Hum Genet
Volume99
Issue1
Pagination40-55
Date Published2016 Jul 07
ISSN1537-6605
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.

DOI10.1016/j.ajhg.2016.05.005
Alternate JournalAm. J. Hum. Genet.
PubMed ID27346686
PubMed Central IDPMC5005441
Grant ListR01 HL112064 / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
UL1 TR000445 / TR / NCATS NIH HHS / United States
R01 HL087698 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
U01 HG004603 / HG / NHGRI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01 HC095160 / HC / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 HD074711 / HD / NICHD NIH HHS / United States
U01 HL072518 / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
N01 HC095159 / HC / NHLBI NIH HHS / United States