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Multiple loci are associated with white blood cell phenotypes.

Publication ,  Journal Article
Nalls, MA; Couper, DJ; Tanaka, T; van Rooij, FJA; Chen, M-H; Smith, AV; Toniolo, D; Zakai, NA; Yang, Q; Greinacher, A; Wood, AR; Garcia, M ...
Published in: PLoS Genet
June 2011

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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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

June 2011

Volume

7

Issue

6

Start / End Page

e1002113

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Polymorphism, Single Nucleotide
  • Phenotype
  • Multigene Family
  • Molecular Epidemiology
  • Leukocytes
  • Leukocyte Count
  • Humans
  • Genome-Wide Association Study
  • Genetic Loci
 

Citation

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Nalls, M. A., Couper, D. J., Tanaka, T., van Rooij, F. J. A., Chen, M.-H., Smith, A. V., … Ganesh, S. K. (2011). Multiple loci are associated with white blood cell phenotypes. PLoS Genet, 7(6), e1002113. https://doi.org/10.1371/journal.pgen.1002113
Nalls, Michael A., David J. Couper, Toshiko Tanaka, Frank J. A. van Rooij, Ming-Huei Chen, Albert V. Smith, Daniela Toniolo, et al. “Multiple loci are associated with white blood cell phenotypes.PLoS Genet 7, no. 6 (June 2011): e1002113. https://doi.org/10.1371/journal.pgen.1002113.
Nalls MA, Couper DJ, Tanaka T, van Rooij FJA, Chen M-H, Smith AV, et al. Multiple loci are associated with white blood cell phenotypes. PLoS Genet. 2011 Jun;7(6):e1002113.
Nalls, Michael A., et al. “Multiple loci are associated with white blood cell phenotypes.PLoS Genet, vol. 7, no. 6, June 2011, p. e1002113. Pubmed, doi:10.1371/journal.pgen.1002113.
Nalls MA, Couper DJ, Tanaka T, van Rooij FJA, Chen M-H, 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, 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 H-E, 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. Multiple loci are associated with white blood cell phenotypes. PLoS Genet. 2011 Jun;7(6):e1002113.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

June 2011

Volume

7

Issue

6

Start / End Page

e1002113

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Polymorphism, Single Nucleotide
  • Phenotype
  • Multigene Family
  • Molecular Epidemiology
  • Leukocytes
  • Leukocyte Count
  • Humans
  • Genome-Wide Association Study
  • Genetic Loci