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

TitleLarge-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.
Publication TypeJournal Article
Year of Publication2016
AuthorsTajuddin SM, Schick UM, Eicher JD, Chami N, Giri A, Brody JA, W Hill D, Kacprowski T, Li J, Lyytikäinen L-P, Manichaikul A, Mihailov E, O'Donoghue ML, Pankratz N, Pazoki R, Polfus LM, Smith A V, Schurmann C, Vacchi-Suzzi C, Waterworth DM, Evangelou E, Yanek LR, Burt A, Chen M-H, van Rooij FJA, Floyd JS, Greinacher A, Harris TB, Highland HM, Lange LA, Liu Y, Mägi R, Nalls MA, Mathias RA, Nickerson DA, Nikus K, Starr JM, Tardif J-C, Tzoulaki I, Edwards DRVelez, Wallentin L, Bartz TM, Becker LC, Denny JC, Raffield LM, Rioux JD, Friedrich N, Fornage M, Gao H, Hirschhorn JN, Liewald DCM, Rich SS, Uitterlinden A, Bastarache L, Becker DM, Boerwinkle E, de Denus S, Bottinger EP, Hayward C, Hofman A, Homuth G, Lange E, Launer LJ, Lehtimäki T, Lu Y, Metspalu A, O'Donnell CJ, Quarells RC, Richard M, Torstenson ES, Taylor KD, Vergnaud A-C, Zonderman AB, Crosslin DR, Deary IJ, Dörr M, Elliott P, Evans MK, Gudnason V, Kähönen M, Psaty BM, Rotter JI, Slater AJ, Dehghan A, White HD, Ganesh SK, Loos RJF, Esko T, Faraday N, Wilson JG, Cushman M, Johnson AD, Edwards TL, Zakai NA, Lettre G, Reiner AP
Secondary AuthorsAuer PL
JournalAm J Hum Genet
Volume99
Issue1
Pagination22-39
Date Published2016 Jul 07
ISSN1537-6605
KeywordsBlood Cell Count, Exome, Genetic Loci, Genetic Pleiotropy, Genome-Wide Association Study, Humans, Immune System Diseases, Leukocytes, Quality Control
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.

DOI10.1016/j.ajhg.2016.05.003
Alternate JournalAm J Hum Genet
PubMed ID27346689
PubMed Central IDPMC5005433
Grant ListR01 HL112064 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
R01 HL122684 / HL / NHLBI NIH HHS / United States
U01 HG008657 / HG / NHGRI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
MR/K026992/1 / / Medical Research Council / United Kingdom
S10 OD018522 / OD / NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 HD074711 / HD / NICHD NIH HHS / United States
MC_PC_U127561128 / / Medical Research Council / United Kingdom
R21 HL121429 / HL / NHLBI NIH HHS / United States
F32 AR059469 / AR / NIAMS NIH HHS / United States
T32 HL007055 / HL / NHLBI NIH HHS / United States
R21 HL121422 / HL / NHLBI NIH HHS / United States