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

Publication ,  Journal Article
Tajuddin, SM; Schick, UM; Eicher, JD; Chami, N; Giri, A; Brody, JA; Hill, WD; Kacprowski, T; Li, J; Lyytikäinen, L-P; Manichaikul, A; Burt, A ...
Published in: Am J Hum Genet
July 7, 2016

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.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

July 7, 2016

Volume

99

Issue

1

Start / End Page

22 / 39

Location

United States

Related Subject Headings

  • Quality Control
  • Leukocytes
  • Immune System Diseases
  • Humans
  • Genome-Wide Association Study
  • Genetics & Heredity
  • Genetic Pleiotropy
  • Genetic Loci
  • Exome
  • Blood Cell Count
 

Citation

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Tajuddin, S. M., Schick, U. M., Eicher, J. D., Chami, N., Giri, A., Brody, J. A., … Auer, P. L. (2016). Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. Am J Hum Genet, 99(1), 22–39. https://doi.org/10.1016/j.ajhg.2016.05.003
Tajuddin, Salman M., Ursula M. Schick, John D. Eicher, Nathalie Chami, Ayush Giri, Jennifer A. Brody, W David Hill, et al. “Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.Am J Hum Genet 99, no. 1 (July 7, 2016): 22–39. https://doi.org/10.1016/j.ajhg.2016.05.003.
Tajuddin SM, Schick UM, Eicher JD, Chami N, Giri A, Brody JA, et al. Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. Am J Hum Genet. 2016 Jul 7;99(1):22–39.
Tajuddin, Salman M., et al. “Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.Am J Hum Genet, vol. 99, no. 1, July 2016, pp. 22–39. Pubmed, doi:10.1016/j.ajhg.2016.05.003.
Tajuddin SM, Schick UM, Eicher JD, Chami N, Giri A, Brody JA, Hill WD, Kacprowski T, Li J, Lyytikäinen L-P, Manichaikul A, Mihailov E, O’Donoghue ML, Pankratz N, Pazoki R, Polfus LM, Smith AV, 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, Velez Edwards DR, 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, Auer PL. Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. Am J Hum Genet. 2016 Jul 7;99(1):22–39.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

July 7, 2016

Volume

99

Issue

1

Start / End Page

22 / 39

Location

United States

Related Subject Headings

  • Quality Control
  • Leukocytes
  • Immune System Diseases
  • Humans
  • Genome-Wide Association Study
  • Genetics & Heredity
  • Genetic Pleiotropy
  • Genetic Loci
  • Exome
  • Blood Cell Count