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Multiple Loci Are Associated with White Blood Cell Phenotypes

Author

Listed:
  • 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

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 Summary: WBC traits are highly variable, moderately heritable, and commonly assayed as part of clinical complete blood count (CBC) examinations. The counts of constituent cell subtypes comprising the WBC count measure are assayed as part of a standard clinical WBC differential test. In this study we employed meta-analytic techniques and identified ten associations with WBC measures at seven genomic loci in a large sample set of over 31,000 participants. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We confirm previous associations of WBC traits with three loci and identified seven novel loci. We also utilize a number of additional analytic methods to infer the functional relatedness of independently implicated loci across WBC phenotypes, as well as investigate direct functional consequences of these loci through analyses of genomic variation affecting the expression of proximal genes in samples of whole blood. In addition, subsequent collaborative efforts with studies of WBC traits in African-American and Japanese cohorts allowed for the investigation of the effects of these genomic variants across populations of diverse continental ancestries.

Suggested Citation

  • 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 G, 2011. "Multiple Loci Are Associated with White Blood Cell Phenotypes," PLOS Genetics, Public Library of Science, vol. 7(6), pages 1-16, June.
  • Handle: RePEc:plo:pgen00:1002113
    DOI: 10.1371/journal.pgen.1002113
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    References listed on IDEAS

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    1. Miriam F. Moffatt & Michael Kabesch & Liming Liang & Anna L. Dixon & David Strachan & Simon Heath & Martin Depner & Andrea von Berg & Albrecht Bufe & Ernst Rietschel & Andrea Heinzmann & Burkard Simma, 2007. "Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma," Nature, Nature, vol. 448(7152), pages 470-473, July.
    2. Soumya Raychaudhuri & Robert M Plenge & Elizabeth J Rossin & Aylwin C Y Ng & International Schizophrenia Consortium & Shaun M Purcell & Pamela Sklar & Edward M Scolnick & Ramnik J Xavier & David Altsh, 2009. "Identifying Relationships among Genomic Disease Regions: Predicting Genes at Pathogenic SNP Associations and Rare Deletions," PLOS Genetics, Public Library of Science, vol. 5(6), pages 1-15, June.
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