Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases
Creators: name: Brody, Jennifer A.
name: Edwards, Todd L.
name: Li, Jin
name: Starr, John M.
name: Boerwinkle, Eric
name: Lu, Yingchang
name: Manichaikul, Ani
name: Johnson, Andrew D.
name: Dehghan, Abbas
name: Hill, W. David
name: Hirschhorn, Joel N.
name: Wilson, James G.
name: Gudnason, Vilmundur
name: Tajuddin, Salman M.
name: Nickerson, Deborah A.
name: Pazoki, Raha
name: Denny, Joshua C.
name: Gao, He
name: Liu, Yongmei
name: Waterworth, Dawn M.
name: Evangelou, Evangelos
name: Slater, Andrew J.
name: Wallentin, Lars
name: Launer, Lenore J.
name: Lettre, Guillaume
name: Pankratz, Nathan
name: Quarells, Rakale C.
name: Cushman, Mary
name: Raffield, Laura M.
name: Harris, Tamara B.
name: Faraday, Nauder
name: Deary, Ian J.
name: Schick, Ursula M.
name: Bastarache, Lisa
name: Bottinger, Erwin P.
name: Rich, Stephen S.
name: Schurmann, Claudia
name: Mathias, Rasika A.
name: Becker, Lewis C.
name: Kacprowski, Tim
name: Hofman, Albert
name: Torstenson, Eric S.
name: Kähönen, Mika
name: Crosslin, David R.
name: Reiner, Alex P.
name: Ganesh, Santhi K.
name: Velez Edwards, Digna R.
name: Mägi, Reedik
name: Greinacher, Andreas
name: O'Donoghue, Michelle L.
name: Vergnaud, Anne-Claire
name: Psaty, Bruce M.
name: Chami, Nathalie
name: Bartz, Traci M.
name: Yanek, Lisa R.
name: Hayward, Caroline
name: Esko, Tõnu
name: Rioux, John D.
name: Taylor, Kent D.
name: van Rooij, Frank J.A.
name: Lange, Ethan
name: Eicher, John D.
name: Highland, Heather M.
name: de Denus, Simon
name: O'Donnell, Chris J.
name: Nalls, Mike A.
name: Lehtimäki, Terho
name: Auer, Paul L.
name: Liewald, David C.M.
name: Polfus, Linda M.
name: Homuth, Georg
name: Nikus, Kjell
name: Mihailov, Evelin
name: Becker, Diane M.
name: Lange, Leslie A.
name: Metspalu, Andres
name: Giri, Ayush
name: Chen, Ming-Huei
name: Rotter, Jerome I.
name: Loos, Ruth J.F.
name: Floyd, James S.
name: Elliott, Paul
name: Zakai, Neil A.
name: Tzoulaki, Ioanna
name: Richard, Melissa
name: Evans, Michele K.
name: Burt, Amber
name: Smith, Albert Vernon
name: Dörr, Marcus
name: Tardif, Jean-Claude
name: Zonderman, Alan B.
name: Uitterlinden, Andre
name: Fornage, Myriam
name: White, Harvey D.
name: Lyytikäinen, Leo-Pekka
name: Friedrich, Nele
name: Vacchi-Suzzi, Caterina
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2016

description: Supplemental Data Supplemental Data include 2 figures, 13 tables, and additional funding information and can be found with this article online at http://dx.doi.org/10.1016/j.ajhg.2016.05.003. Supplemental Data Document S1. Figures S1 and S2, Tables S3–S5, S7, S8, and S10–S12, and Additional Funding Information Download Table S1. Information on Genotyping Methods, Quality Control of SNPs, and Statistical Analyses for Exomechip Study Download Table S2. Description and Design of Studies Participating in the Blood-Cell Consortium with White Blood Cell Trait Data Download Table S6. List of All White Blood Cell Trait Loci that Reached Exome-wide Significance in the Discovery Meta-analysis Stage Download Table S9. Comparison of Allele Frequencies and Directions of Effect across Ancestries of White Blood Cell Trait Loci Download Table S13. Expression Quantitative Trait Loci Lookups of White Blood Cell Trait Variants Identified in the Present Study Download Document S2. Article plus Supplemental Data Download Web Resources 1000 Genomes, http://www.1000genomes.org BCX ExomeChip association results, http://www.mhi-humangenetics.org/en/resources CheckVCF, https://github.com/zhanxw/checkVCF GRASP, http://grasp.nhlbi.nih.gov/Overview.aspx HPC @ NIH, http://hpc.nih.gov OMIM, http://www.omim.org/ R statistical software, http://www.r-project.org/ RareMETALS, http://genome.sph.umich.edu/wiki/RareMETALS RareMetalWorker, http://genome.sph.umich.edu/wiki/RAREMETALWORKER RvTests, http://genome.sph.umich.edu/wiki/RvTests 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.