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

Abstract

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

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

“…18,19 The shared genetic associations with the two other primary blood cell lineages further supports other studies proposing that mechanisms that govern platelet size and number also influence RBC and WBC traits. 61 In BCX analyses, rs1050331 in the 3 0 UTR of ZMIZ2 was associated with increased PLT, mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV), as well as with decreased WBC count.…”

“…There was substantial overlap of our platelet associations with concurrent Exomechip association findings for RBC and WBC traits, indicating shared genetic influence on regulatory and functional mechanisms among the three different blood cell lineages. 18,19 More surprisingly, we observed shared associations of platelet and lipids loci. The identification of shared blood cell and lipids associations as well as identifying genes with entirely new associations reveals candidates for further examination in order to elucidate the mechanisms underlying platelet development and function.…”

“…61 In BCX analyses, rs1050331 in the 3 0 UTR of ZMIZ2 was associated with increased PLT, mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV), as well as with decreased WBC count. 18,19 rs1050331 is also an eQTL for ZMIZ2 expression in whole blood (Table S21). 62 There are known sex differences in cell counts, with females consistently having higher PLT and mixed results on MPV.…”

“…As the BCX is interested in the genetics of common hematological measures, our collaborative group is divided into three main working groups: RBC, WBC, and platelet. 18,19 For the platelet working group, our sample is comprised of 157,293 participants from 26 discovery and replication cohorts of five ancestries: European (EA), African American (AA), Hispanic, East Asian, and South Asian. Detailed descriptions of the participating cohorts are provided in the Tables S1-S4.…”

“…Loos, 13 Albert Vernon Smith, 59,60 Tamara B. Harris, 61 Lenore J. Launer, 61 Vilmundur Gudnason, 59,60 Digna R. Velez Edwards, 62 Eric S. Torstenson, 19 Yongmei Liu, 63 Russell P. Tracy, 64 Jerome I. Rotter, 65,66 Stephen S. Rich, 22 Heather M. Highland, 67,68 Eric Boerwinkle, 18,69 Jin Li, 70 Ethan Lange, 21,71 James G. Wilson, 72 Evelin Mihailov, 73 Reedik Mägi, 73 Joel Hirschhorn, 7,74 Andres Metspalu, 73 Tõnu Esko, 7,73 Caterina Vacchi-Suzzi, 75 Mike A. Nalls, 76 Alan B. Zonderman, 12 Michele K. Evans, 12 Gunnar Engström, 77,78 Marju Orho-Melander, 77 We thank all participants and study coordinating centers. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the NIH, or the U.S. Department of Health and Human Services.…”