Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals
File(s)
Author(s)
Type
Journal Article
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.
Date Issued
2016-06-23
Online Publication Date
2016-12-23T07:00:13Z
Date Acceptance
2016-05-03
ISSN
1537-6605
Publisher
Elsevier
Start Page
40
End Page
55
Journal / Book Title
American Journal of Human Genetics
Volume
99
Issue
1
Copyright Statement
© 2016 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Source Database
pubmed
Sponsor
Home Office
National Institute for Health Research
Medical Research Council (MRC)
Identifier
S0002-9297(16)30139-2
Grant Number
PG0484
RDC01 79560
MR/L01341X/1
Subjects
Global Lipids Genetics Consortium
CARDIoGRAM Exome Consortium
Myocardial Infarction Genetics Consortium
Genetics & Heredity
06 Biological Sciences
11 Medical And Health Sciences
Publication Status
Published