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Multiple loci are associated with white blood cell phenotypes.

TitleMultiple loci are associated with white blood cell phenotypes.
Publication TypeJournal Article
Year of Publication2011
AuthorsNalls 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, L Cupples A, 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 S L, Coresh J, Wichmann H-E, Menzel S, Lin JP, 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
JournalPLoS Genet
Volume7
Issue6
Paginatione1002113
Date Published2011 Jun
ISSN1553-7404
KeywordsGenetic Loci, Genome-Wide Association Study, Humans, Leukocyte Count, Leukocytes, Molecular Epidemiology, Multigene Family, Phenotype, Polymorphism, Single Nucleotide, Ubiquitin-Protein Ligases
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.

DOI10.1371/journal.pgen.1002113
Alternate JournalPLoS Genet
PubMed ID21738480
PubMed Central IDPMC3128114
Grant ListR01 AG024233 / AG / NIA NIH HHS / United States
N01HC55020 / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
R01HL86694 / HL / NHLBI NIH HHS / United States
32105-6 / / PHS HHS / United States
N01-HC-45205 / HC / NHLBI NIH HHS / United States
N01-AG-821336 / AG / NIA NIH HHS / United States
Z01 AG000513 / / Intramural NIH HHS / United States
N01AG12100 / AG / NIA NIH HHS / United States
N01-HC-05187 / HC / NHLBI NIH HHS / United States
N01-HC-55017 / HC / NHLBI NIH HHS / United States
R01 HL087698 / HL / NHLBI NIH HHS / United States
Z01 AG000932 / / Intramural NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
R01 NR008153 / NR / NINR NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
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R01 AG24233-01 / AG / NIA NIH HHS / United States
N01-HC-48047 / HC / NHLBI NIH HHS / United States
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HL085251 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01HC45205 / HL / NHLBI NIH HHS / United States
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R01 MD009164 / MD / NIMHD NIH HHS / United States
R01 HL085251 / HL / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
42107-26 / / PHS HHS / United States
32115 / / PHS HHS / United States
N01-HC-45204 / HC / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
R01 HL-071862 / HL / NHLBI NIH HHS / United States
G0000111 / / Medical Research Council / United Kingdom
1R01AG032098-01A1 / AG / NIA NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
N01-HC-95095 / HC / NHLBI NIH HHS / United States
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M01-RR000052 / RR / NCRR NIH HHS / United States
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N01 AG062106 / AG / NIA NIH HHS / United States
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HHSN268200625226C / / PHS HHS / United States
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32100-2 / / PHS HHS / United States
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HHSN268200782096C / HG / NHGRI NIH HHS / United States
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32108-9 / / PHS HHS / United States
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N01HC55016 / HL / NHLBI NIH HHS / United States
G20234 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
RG/09/012/28096 / / British Heart Foundation / United Kingdom
U01 HL072518 / HL / NHLBI NIH HHS / United States
N01-HC-95171 / HC / NHLBI NIH HHS / United States
N01HC48050 / HL / NHLBI NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
R01 HL087698-01 / HL / NHLBI NIH HHS / United States
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R01 NR08153 / NR / NINR NIH HHS / United States
N01-HC-95172 / HC / NHLBI NIH HHS / United States
N01-AG-916413 / AG / NIA NIH HHS / United States
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076113/C/04/Z / WT_ / Wellcome Trust / United Kingdom
/ / Wellcome Trust / United Kingdom
MC_U105260799 / / Medical Research Council / United Kingdom
N01-HC-95100 / HC / NHLBI NIH HHS / United States
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32122 / / PHS HHS / United States
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44221 / / PHS HHS / United States
091746/Z/10/Z / WT_ / Wellcome Trust / United Kingdom
32111-13 / / PHS HHS / United States
N01-HC-95170 / HC / NHLBI NIH HHS / United States
N01WH22110 / WH / WHI NIH HHS / United States
K23 AG000932 / AG / NIA NIH HHS / United States
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R01HL086694 / HL / NHLBI NIH HHS / United States
N01-HC-65226 / HC / NHLBI NIH HHS / United States
N01HC95172 / HL / NHLBI NIH HHS / United States