Multiple loci are associated with white blood cell phenotypes

Michael A. Nalls; David J. Couper; Toshiko Tanaka; Frank J A van Rooij; Ming Huei Chen; Albert V. Smith; Daniela Toniolo; Neil A. Zakai; Qiong Yang; Andreas Greinacher; Andrew R. Wood; Melissa Garcia; Paolo Gasparini; Yongmei Liu; Thomas Lumley; Aaron R. Folsom; Alex P. Reiner; Christian Gieger; Vasiliki Lagou; Janine F. Felix; Henry Völzke; Natalia A. Gouskova; Alessandro Biffi; Angela Döring; Uwe Völker; Sean Chong; Kerri L. Wiggins; Augusto Rendon; Abbas Dehghan; Matt Moore; Kent Taylor; James G. Wilson; Guillaume Lettre; Albert Hofman; Joshua C. Bis; Nicola Pirastu; Caroline S. Fox; Christa Meisinger; Jennifer Sambrook; Sampath Arepalli; Matthias Nauck; Holger Prokisch; Jonathan Stephens; Nicole L. Glazer; L. Adrienne Cupples; Yukinori Okada; Atsushi Takahashi; Yoichiro Kamatani; Koichi Matsuda; Tatsuhiko Tsunoda; Toshihiro Tanaka; Michiaki Kubo; Yusuke Nakamura; Kazuhiko Yamamoto; Naoyuki Kamatani; Michael Stumvoll; Anke Tönjes; Inga Prokopenko; Thomas Illig; Kushang V. Patel; Stephen F. Garner; Brigitte Kuhnel; Massimo Mangino; Ben A. Oostra; Swee Lay Thein; Josef Coresh; H. Erich Wichmann; Stephan Menzel; JingPing Lin; Giorgio Pistis; André G. Uitterlinden; Tim D. Spector; Alexander Teumer; Gudny Eiriksdottir; Vilmundur Gudnason; Stefania Bandinelli; Timothy M. Frayling; Aravinda Chakravarti; Cornelia M. van Duijn; David Melzer; Willem H. Ouwehand; Daniel Levy; Eric Boerwinkle; Andrew B. Singleton; Dena G. Hernandez; Dan L. Longo; Nicole Soranzo; Jacqueline C M Witteman; Bruce M. Psaty; Luigi Ferrucci; Tamara B. Harris; Christopher J. O'Donnell; Santhi K. Ganesh

doi:10.1371/journal.pgen.1002113

Multiple loci are associated with white blood cell phenotypes

Michael A. Nalls, David J. Couper, Toshiko Tanaka, Frank J A van Rooij, Ming Huei Chen, Albert V. Smith, Daniela Toniolo, Neil A. Zakai, Qiong Yang, Andreas Greinacher, Andrew R. Wood, Melissa Garcia, Paolo Gasparini, Yongmei Liu, Thomas Lumley, Aaron R. Folsom, Alex P. Reiner, Christian Gieger, Vasiliki Lagou, Janine F. FelixHenry Völzke, Natalia A. Gouskova, Alessandro Biffi, Angela Döring, Uwe Völker, Sean Chong, Kerri L. Wiggins, Augusto Rendon, Abbas Dehghan, Matt Moore, Kent Taylor, James G. Wilson, Guillaume Lettre, Albert Hofman, Joshua C. Bis, Nicola Pirastu, Caroline S. Fox, Christa Meisinger, Jennifer Sambrook, Sampath Arepalli, Matthias Nauck, Holger Prokisch, Jonathan Stephens, Nicole L. Glazer, L. Adrienne Cupples, Yukinori Okada, Atsushi Takahashi, Yoichiro Kamatani, Koichi Matsuda, Tatsuhiko Tsunoda, Toshihiro Tanaka, Michiaki Kubo, Yusuke Nakamura, Kazuhiko Yamamoto, Naoyuki Kamatani, Michael Stumvoll, Anke Tönjes, Inga Prokopenko, Thomas Illig, Kushang V. Patel, Stephen F. Garner, Brigitte Kuhnel, Massimo Mangino, Ben A. Oostra, Swee Lay Thein, Josef Coresh, H. Erich Wichmann, Stephan Menzel, JingPing Lin, Giorgio Pistis, André G. Uitterlinden, Tim D. Spector, Alexander Teumer, Gudny Eiriksdottir, Vilmundur Gudnason, Stefania Bandinelli, Timothy M. Frayling, Aravinda Chakravarti, Cornelia M. van Duijn, David Melzer, Willem H. Ouwehand, Daniel Levy, Eric Boerwinkle, Andrew B. Singleton, Dena G. Hernandez, Dan L. Longo, Nicole Soranzo, Jacqueline C M Witteman, Bruce M. Psaty, Luigi Ferrucci, Tamara B. Harris, Christopher J. O'Donnell, Santhi K. Ganesh

Epidemiology

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Abstract

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count-3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

Original language	English (US)
Article number	e1002113
Journal	PLoS genetics
Volume	7
Issue number	6
DOIs	https://doi.org/10.1371/journal.pgen.1002113
State	Published - Jun 2011

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Nalls, M. A., Couper, D. J., Tanaka, T., van Rooij, F. J. A., Chen, M. H., Smith, A. V., Toniolo, D., Zakai, N. A., Yang, Q., Greinacher, A., Wood, A. R., Garcia, M., Gasparini, P., Liu, Y., Lumley, T., Folsom, A. R., Reiner, A. P., Gieger, C., Lagou, V., ... Ganesh, S. K. (2011). Multiple loci are associated with white blood cell phenotypes. PLoS genetics, 7(6), Article e1002113. https://doi.org/10.1371/journal.pgen.1002113

Nalls, MA, Couper, DJ, Tanaka, T, van Rooij, FJA, Chen, MH, Smith, AV, Toniolo, D, Zakai, NA, Yang, Q, Greinacher, A, Wood, AR, Garcia, M, Gasparini, P, Liu, Y, Lumley, T, Folsom, AR, Reiner, AP, Gieger, C, Lagou, V, Felix, JF, Völzke, H, Gouskova, NA, Biffi, A, Döring, A, Völker, U, Chong, S, Wiggins, KL, Rendon, A, Dehghan, A, Moore, M, Taylor, K, Wilson, JG, Lettre, G, Hofman, A, Bis, JC, Pirastu, N, Fox, CS, Meisinger, C, Sambrook, J, Arepalli, S, Nauck, M, Prokisch, H, Stephens, J, Glazer, NL, Cupples, LA, Okada, Y, Takahashi, A, Kamatani, Y, Matsuda, K, Tsunoda, T, Tanaka, T, Kubo, M, Nakamura, Y, Yamamoto, K, Kamatani, N, Stumvoll, M, Tönjes, A, Prokopenko, I, Illig, T, Patel, KV, Garner, SF, Kuhnel, B, Mangino, M, Oostra, BA, Thein, SL, Coresh, J, Wichmann, HE, Menzel, S, Lin, J, Pistis, G, Uitterlinden, AG, Spector, TD, Teumer, A, Eiriksdottir, G, Gudnason, V, Bandinelli, S, Frayling, TM, Chakravarti, A, van Duijn, CM, Melzer, D, Ouwehand, WH, Levy, D, Boerwinkle, E, Singleton, AB, Hernandez, DG, Longo, DL, Soranzo, N, Witteman, JCM, Psaty, BM, Ferrucci, L, Harris, TB, O'Donnell, CJ & Ganesh, SK 2011, 'Multiple loci are associated with white blood cell phenotypes', PLoS genetics, vol. 7, no. 6, e1002113. https://doi.org/10.1371/journal.pgen.1002113

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title = "Multiple loci are associated with white blood cell phenotypes",

abstract = "White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count-3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.",

author = "Nalls, {Michael A.} and Couper, {David J.} and Toshiko Tanaka and {van Rooij}, {Frank J A} and Chen, {Ming Huei} and Smith, {Albert V.} and Daniela Toniolo and Zakai, {Neil A.} and Qiong Yang and Andreas Greinacher and Wood, {Andrew R.} and Melissa Garcia and Paolo Gasparini and Yongmei Liu and Thomas Lumley and Folsom, {Aaron R.} and Reiner, {Alex P.} and Christian Gieger and Vasiliki Lagou and Felix, {Janine F.} and Henry V{\"o}lzke and Gouskova, {Natalia A.} and Alessandro Biffi and Angela D{\"o}ring and Uwe V{\"o}lker and Sean Chong and Wiggins, {Kerri L.} and Augusto Rendon and Abbas Dehghan and Matt Moore and Kent Taylor and Wilson, {James G.} and Guillaume Lettre and Albert Hofman and Bis, {Joshua C.} and Nicola Pirastu and Fox, {Caroline S.} and Christa Meisinger and Jennifer Sambrook and Sampath Arepalli and Matthias Nauck and Holger Prokisch and Jonathan Stephens and Glazer, {Nicole L.} and Cupples, {L. Adrienne} and Yukinori Okada and Atsushi Takahashi and Yoichiro Kamatani and Koichi Matsuda and Tatsuhiko Tsunoda and Toshihiro Tanaka and Michiaki Kubo and Yusuke Nakamura and Kazuhiko Yamamoto and Naoyuki Kamatani and Michael Stumvoll and Anke T{\"o}njes and Inga Prokopenko and Thomas Illig and Patel, {Kushang V.} and Garner, {Stephen F.} and Brigitte Kuhnel and Massimo Mangino and Oostra, {Ben A.} and Thein, {Swee Lay} and Josef Coresh and Wichmann, {H. Erich} and Stephan Menzel and JingPing Lin and Giorgio Pistis and Uitterlinden, {Andr{\'e} G.} and Spector, {Tim D.} and Alexander Teumer and Gudny Eiriksdottir and Vilmundur Gudnason and Stefania Bandinelli and Frayling, {Timothy M.} and Aravinda Chakravarti and {van Duijn}, {Cornelia M.} and David Melzer and Ouwehand, {Willem H.} and Daniel Levy and Eric Boerwinkle and Singleton, {Andrew B.} and Hernandez, {Dena G.} and Longo, {Dan L.} and Nicole Soranzo and Witteman, {Jacqueline C M} and Psaty, {Bruce M.} and Luigi Ferrucci and Harris, {Tamara B.} and O'Donnell, {Christopher J.} and Ganesh, {Santhi K.}",

year = "2011",

month = jun,

doi = "10.1371/journal.pgen.1002113",

language = "English (US)",

volume = "7",

journal = "PLoS genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "6",

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TY - JOUR

T1 - Multiple loci are associated with white blood cell phenotypes

AU - Nalls, Michael A.

AU - Couper, David J.

AU - Tanaka, Toshiko

AU - van Rooij, Frank J A

AU - Chen, Ming Huei

AU - Smith, Albert V.

AU - Toniolo, Daniela

AU - Zakai, Neil A.

AU - Yang, Qiong

AU - Greinacher, Andreas

AU - Wood, Andrew R.

AU - Garcia, Melissa

AU - Gasparini, Paolo

AU - Liu, Yongmei

AU - Lumley, Thomas

AU - Folsom, Aaron R.

AU - Reiner, Alex P.

AU - Gieger, Christian

AU - Lagou, Vasiliki

AU - Felix, Janine F.

AU - Völzke, Henry

AU - Gouskova, Natalia A.

AU - Biffi, Alessandro

AU - Döring, Angela

AU - Völker, Uwe

AU - Chong, Sean

AU - Wiggins, Kerri L.

AU - Rendon, Augusto

AU - Dehghan, Abbas

AU - Moore, Matt

AU - Taylor, Kent

AU - Wilson, James G.

AU - Lettre, Guillaume

AU - Hofman, Albert

AU - Bis, Joshua C.

AU - Pirastu, Nicola

AU - Fox, Caroline S.

AU - Meisinger, Christa

AU - Sambrook, Jennifer

AU - Arepalli, Sampath

AU - Nauck, Matthias

AU - Prokisch, Holger

AU - Stephens, Jonathan

AU - Glazer, Nicole L.

AU - Cupples, L. Adrienne

AU - Okada, Yukinori

AU - Takahashi, Atsushi

AU - Kamatani, Yoichiro

AU - Matsuda, Koichi

AU - Tsunoda, Tatsuhiko

AU - Tanaka, Toshihiro

AU - Kubo, Michiaki

AU - Nakamura, Yusuke

AU - Yamamoto, Kazuhiko

AU - Kamatani, Naoyuki

AU - Stumvoll, Michael

AU - Tönjes, Anke

AU - Prokopenko, Inga

AU - Illig, Thomas

AU - Patel, Kushang V.

AU - Garner, Stephen F.

AU - Kuhnel, Brigitte

AU - Mangino, Massimo

AU - Oostra, Ben A.

AU - Thein, Swee Lay

AU - Coresh, Josef

AU - Wichmann, H. Erich

AU - Menzel, Stephan

AU - Lin, JingPing

AU - Pistis, Giorgio

AU - Uitterlinden, André G.

AU - Spector, Tim D.

AU - Teumer, Alexander

AU - Eiriksdottir, Gudny

AU - Gudnason, Vilmundur

AU - Bandinelli, Stefania

AU - Frayling, Timothy M.

AU - Chakravarti, Aravinda

AU - van Duijn, Cornelia M.

AU - Melzer, David

AU - Ouwehand, Willem H.

AU - Levy, Daniel

AU - Boerwinkle, Eric

AU - Singleton, Andrew B.

AU - Hernandez, Dena G.

AU - Longo, Dan L.

AU - Soranzo, Nicole

AU - Witteman, Jacqueline C M

AU - Psaty, Bruce M.

AU - Ferrucci, Luigi

AU - Harris, Tamara B.

AU - O'Donnell, Christopher J.

AU - Ganesh, Santhi K.

PY - 2011/6

Y1 - 2011/6

N2 - White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count-3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

AB - White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count-3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

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DO - 10.1371/journal.pgen.1002113

M3 - Article

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AN - SCOPUS:79959824142

SN - 1553-7390

VL - 7

JO - PLoS genetics

JF - PLoS genetics

IS - 6

M1 - e1002113

ER -

Multiple loci are associated with white blood cell phenotypes

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