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

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

doi:10.1016/j.ajhg.2016.05.003

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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

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.

Original language	English (US)
Pages (from-to)	22-39
Number of pages	18
Journal	American journal of human genetics
Volume	99
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2016.05.003
State	Published - Jul 7 2016

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Tajuddin, S. M., Schick, U. M., Eicher, J. D., Chami, N., Giri, A., Brody, J. A., Hill, W. D., Kacprowski, T., Li, J., Lyytikäinen, L. P., Manichaikul, A., Mihailov, E., O'Donoghue, M. L., Pankratz, N., Pazoki, R., Polfus, L. M., Smith, A. V., Schurmann, C., Vacchi-Suzzi, C., ... Auer, P. L. (2016). Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. American journal of human genetics, 99(1), 22-39. https://doi.org/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, LP, 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, MH, 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, JC, 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, AC, 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 2016, 'Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases', American journal of human genetics, vol. 99, no. 1, pp. 22-39. https://doi.org/10.1016/j.ajhg.2016.05.003

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title = "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.",

author = "Tajuddin, {Salman M.} and Schick, {Ursula M.} and Eicher, {John D.} and Nathalie Chami and Ayush Giri and Brody, {Jennifer A.} and Hill, {W. David} and Tim Kacprowski and Jin Li and Lyytik{\"a}inen, {Leo Pekka} and Ani Manichaikul and Evelin Mihailov and O'Donoghue, {Michelle L.} and Nathan Pankratz and Raha Pazoki and Polfus, {Linda M.} and Smith, {Albert Vernon} and Claudia Schurmann and Caterina Vacchi-Suzzi and Waterworth, {Dawn M.} and Evangelos Evangelou and Yanek, {Lisa R.} and Amber Burt and Chen, {Ming Huei} and {van Rooij}, {Frank J.A.} and Floyd, {James S.} and Andreas Greinacher and Harris, {Tamara B.} and Highland, {Heather M.} and Lange, {Leslie A.} and Yongmei Liu and Reedik M{\"a}gi and Nalls, {Mike A.} and Mathias, {Rasika A.} and Nickerson, {Deborah A.} and Kjell Nikus and Starr, {John M.} and Tardif, {Jean Claude} and Ioanna Tzoulaki and {Velez Edwards}, {Digna R.} and Lars Wallentin and Bartz, {Traci M.} and Becker, {Lewis C.} and Denny, {Joshua C.} and Raffield, {Laura M.} and Rioux, {John D.} and Nele Friedrich and Myriam Fornage and He Gao and Hirschhorn, {Joel N.} and Liewald, {David C.M.} and Rich, {Stephen S.} and Andre Uitterlinden and Lisa Bastarache and Becker, {Diane M.} and Eric Boerwinkle and {de Denus}, Simon and Bottinger, {Erwin P.} and Caroline Hayward and Albert Hofman and Georg Homuth and Ethan Lange and Launer, {Lenore J.} and Terho Lehtim{\"a}ki and Yingchang Lu and Andres Metspalu and O'Donnell, {Chris J.} and Quarells, {Rakale C.} and Melissa Richard and Torstenson, {Eric S.} and Taylor, {Kent D.} and Vergnaud, {Anne Claire} and Zonderman, {Alan B.} and Crosslin, {David R.} and Deary, {Ian J.} and Marcus D{\"o}rr and Paul Elliott and Evans, {Michele K.} and Vilmundur Gudnason and Mika K{\"a}h{\"o}nen and Psaty, {Bruce M.} and Rotter, {Jerome I.} and Slater, {Andrew J.} and Abbas Dehghan and White, {Harvey D.} and Ganesh, {Santhi K.} and Loos, {Ruth J.F.} and T{\~o}nu Esko and Nauder Faraday and Wilson, {James G.} and Mary Cushman and Johnson, {Andrew D.} and Edwards, {Todd L.} and Zakai, {Neil A.} and Guillaume Lettre and Reiner, {Alex P.} and Auer, {Paul L.}",

note = "Publisher Copyright: {\textcopyright} 2016 American Society of Human Genetics",

year = "2016",

month = jul,

day = "7",

doi = "10.1016/j.ajhg.2016.05.003",

language = "English (US)",

volume = "99",

pages = "22--39",

journal = "American journal of human genetics",

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TY - JOUR

T1 - Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

AU - Tajuddin, Salman M.

AU - Schick, Ursula M.

AU - Eicher, John D.

AU - Chami, Nathalie

AU - Giri, Ayush

AU - Brody, Jennifer A.

AU - Hill, W. David

AU - Kacprowski, Tim

AU - Li, Jin

AU - Lyytikäinen, Leo Pekka

AU - Manichaikul, Ani

AU - Mihailov, Evelin

AU - O'Donoghue, Michelle L.

AU - Pankratz, Nathan

AU - Pazoki, Raha

AU - Polfus, Linda M.

AU - Smith, Albert Vernon

AU - Schurmann, Claudia

AU - Vacchi-Suzzi, Caterina

AU - Waterworth, Dawn M.

AU - Evangelou, Evangelos

AU - Yanek, Lisa R.

AU - Burt, Amber

AU - Chen, Ming Huei

AU - van Rooij, Frank J.A.

AU - Floyd, James S.

AU - Greinacher, Andreas

AU - Harris, Tamara B.

AU - Highland, Heather M.

AU - Lange, Leslie A.

AU - Liu, Yongmei

AU - Mägi, Reedik

AU - Nalls, Mike A.

AU - Mathias, Rasika A.

AU - Nickerson, Deborah A.

AU - Nikus, Kjell

AU - Starr, John M.

AU - Tardif, Jean Claude

AU - Tzoulaki, Ioanna

AU - Velez Edwards, Digna R.

AU - Wallentin, Lars

AU - Bartz, Traci M.

AU - Becker, Lewis C.

AU - Denny, Joshua C.

AU - Raffield, Laura M.

AU - Rioux, John D.

AU - Friedrich, Nele

AU - Fornage, Myriam

AU - Gao, He

AU - Hirschhorn, Joel N.

AU - Liewald, David C.M.

AU - Rich, Stephen S.

AU - Uitterlinden, Andre

AU - Bastarache, Lisa

AU - Becker, Diane M.

AU - Boerwinkle, Eric

AU - de Denus, Simon

AU - Bottinger, Erwin P.

AU - Hayward, Caroline

AU - Hofman, Albert

AU - Homuth, Georg

AU - Lange, Ethan

AU - Launer, Lenore J.

AU - Lehtimäki, Terho

AU - Lu, Yingchang

AU - Metspalu, Andres

AU - O'Donnell, Chris J.

AU - Quarells, Rakale C.

AU - Richard, Melissa

AU - Torstenson, Eric S.

AU - Taylor, Kent D.

AU - Vergnaud, Anne Claire

AU - Zonderman, Alan B.

AU - Crosslin, David R.

AU - Deary, Ian J.

AU - Dörr, Marcus

AU - Elliott, Paul

AU - Evans, Michele K.

AU - Gudnason, Vilmundur

AU - Kähönen, Mika

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Slater, Andrew J.

AU - Dehghan, Abbas

AU - White, Harvey D.

AU - Ganesh, Santhi K.

AU - Loos, Ruth J.F.

AU - Esko, Tõnu

AU - Faraday, Nauder

AU - Wilson, James G.

AU - Cushman, Mary

AU - Johnson, Andrew D.

AU - Edwards, Todd L.

AU - Zakai, Neil A.

AU - Lettre, Guillaume

AU - Reiner, Alex P.

AU - Auer, Paul L.

PY - 2016/7/7

Y1 - 2016/7/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84989906739&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84989906739&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2016.05.003

DO - 10.1016/j.ajhg.2016.05.003

M3 - Article

C2 - 27346689

AN - SCOPUS:84989906739

SN - 0002-9297

VL - 99

SP - 22

EP - 39

JO - American journal of human genetics

JF - American journal of human genetics

IS - 1

ER -

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

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