Multiple loci are associated with white blood cell phenotypes.

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 1...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/4609dc82c7f6406db499ad223bf6fcca
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spelling	oai:doaj.org-article:4609dc82c7f6406db499ad223bf6fcca2021-11-18T06:17:17ZMultiple loci are associated with white blood cell phenotypes.1553-73901553-740410.1371/journal.pgen.1002113https://doaj.org/article/4609dc82c7f6406db499ad223bf6fcca2011-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21738480/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404White 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.Michael A NallsDavid J CouperToshiko TanakaFrank J A van RooijMing-Huei ChenAlbert V SmithDaniela TonioloNeil A ZakaiQiong YangAndreas GreinacherAndrew R WoodMelissa GarciaPaolo GaspariniYongmei LiuThomas LumleyAaron R FolsomAlex P ReinerChristian GiegerVasiliki LagouJanine F FelixHenry VölzkeNatalia A GouskovaAlessandro BiffiAngela DöringUwe VölkerSean ChongKerri L WigginsAugusto RendonAbbas DehghanMatt MooreKent TaylorJames G WilsonGuillaume LettreAlbert HofmanJoshua C BisNicola PirastuCaroline S FoxChrista MeisingerJennifer SambrookSampath ArepalliMatthias NauckHolger ProkischJonathan StephensNicole L GlazerL Adrienne CupplesYukinori OkadaAtsushi TakahashiYoichiro KamataniKoichi MatsudaTatsuhiko TsunodaToshihiro TanakaMichiaki KuboYusuke NakamuraKazuhiko YamamotoNaoyuki KamataniMichael StumvollAnke TönjesInga ProkopenkoThomas IlligKushang V PatelStephen F GarnerBrigitte KuhnelMassimo ManginoBen A OostraSwee Lay TheinJosef CoreshH-Erich WichmannStephan MenzelJingPing LinGiorgio PistisAndré G UitterlindenTim D SpectorAlexander TeumerGudny EiriksdottirVilmundur GudnasonStefania BandinelliTimothy M FraylingAravinda ChakravartiCornelia M van DuijnDavid MelzerWillem H OuwehandDaniel LevyEric BoerwinkleAndrew B SingletonDena G HernandezDan L LongoNicole SoranzoJacqueline C M WittemanBruce M PsatyLuigi FerrucciTamara B HarrisChristopher J O'DonnellSanthi K GaneshPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 7, Iss 6, p e1002113 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 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 Multiple loci are associated with white blood cell phenotypes.
description	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.
format	article
author	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
author_facet	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
author_sort	Michael A Nalls
title	Multiple loci are associated with white blood cell phenotypes.
title_short	Multiple loci are associated with white blood cell phenotypes.
title_full	Multiple loci are associated with white blood cell phenotypes.
title_fullStr	Multiple loci are associated with white blood cell phenotypes.
title_full_unstemmed	Multiple loci are associated with white blood cell phenotypes.
title_sort	multiple loci are associated with white blood cell phenotypes.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/4609dc82c7f6406db499ad223bf6fcca
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Multiple loci are associated with white blood cell phenotypes.

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