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.

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

“…Our meta-analyses confirmed two known independent ANK1 variants associated with MCHC: an intronic SNP (rs4737009, MAF ¼ 19.8%, p ¼ 1.3 3 10 À8 ) and a low-frequency missense variant (rs34664882, p.Ala1462Val, MAF ¼ 2.9%, p ¼ 1.7 3 10 À16 ) (Table S5; N.P., U.M.S., J.B.-J., and M.-H.C., unpublished data). 17 In the accompanying BCX PLT article, 20 we report that the same MAP1A rs55707100 allele (p.Pro2349Leu [c.7046C>T]) associated here with decreased HGB concentration is also associated with increased PLT count. Furthermore, recent studies have identified associations between rs55707100 and HDL-cholesterol and triglyceride levels (S. Mukherjee, 2015, ASHG, conference).…”

“…BCX is interested in the genetics of all main hematological measures and is divided into three main working groups: RBC, white blood cell (WBC), 21 and platelet (PLT). 20 For the RBC working group, we analyzed seven traits available in up to 130,273 individuals: RBC count (310 12 /L), HGB (g/dL), HCT (%), MCV (fL), MCH (pg), MCHC (g/dL), and RDW (%) ( Table S2). The BCX procedures were in accordance with the institutional and national ethical standards of the responsible committees and proper informed consent was obtained.…”

“…Using an exome array, we previously performed an association study for HGB and HCT in 31,340 European-ancestry individuals and identified rare coding or splice site variants in the erythropoietin and b-globin genes. 19 Within the framework of the BloodCell Consortium (BCX), 20,21 we now report a larger genotyping-based exome survey of seven RBC traits conducted in up to 130,273 individuals, including 23,896 participants of non-European ancestry. With this experiment, our initial goals were to expand the list of rare and lowfrequency coding or splice site variants associated with RBC traits and to explore whether the exome array can complement the GWAS approach to fine map RBC causal genes.…”

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

“…Similarly, to assess whether the WBC variants were associated with other blood cell traits, we obtained effect sizes and p values for these variants from RBC-and platelet-related traits exome array analyses within the BCX consortium. 32,33 …”

Genomics and transcriptomics of megakaryocytes and platelets: Implications for health and disease

“…demonstrated association of rare variants in BAK1, MPL, ITGB3, CD109 , and CD36 with platelet count and MPV, which led to the development of the Exomechip, a quick genotyping method enriched in rare coding variants demonstrated in previous WES studies and common SNP variants identified in GWAS studies. The ability to increase sample size enabled the Exomechip technology to identify novel gene associations, including JAK2 , TUBB1 , MAP1A , ZMIZ2 , PEAR1 , and PACSIN2 34, 35…”