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, Jing Ping 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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Article numbere1002113
JournalPLoS genetics
Volume7
Issue number6
DOIs
StatePublished - Jun 1 2011

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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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), [e1002113]. https://doi.org/10.1371/journal.pgen.1002113