Genetic variants associated with the white blood cell count in 13,923 subjects in the eMERGE Network

David R. Crosslin, Andrew McDavid, Noah Weston, Sarah C. Nelson, Xiuwen Zheng, Eugene Hart, Mariza De Andrade, Iftikhar Jan Kullo, Catherine A. McCarty, Kimberly F. Doheny, Elizabeth Pugh, Abel Kho, M. Geoffrey Hayes, Stephanie Pretel, Alexander Saip, Marylyn D. Ritchie, Dana C. Crawford, Paul K. Crane, Katherine Newton, Rongling LiDaniel B. Mirel, Andrew Crenshaw, Eric B. Larson, Chris S. Carlson, Gail P. Jarvik

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Abstract

White blood cell count (WBC) is unique among identified inflammatory predictors of chronic disease in that it is routinely measured in asymptomatic patients in the course of routine patient care. We led a genome-wide association analysis to identify variants associated with WBC levels in 13,923 subjects in the electronic Medical Records and Genomics (eMERGE) Network. We identified two regions of interest that were each unique to subjects of genetically determined ancestry to the African continent (AA) or to the European continent (EA). WBC varies among different ancestry groups. Despite being ancestry specific, these regions were identifiable in the combined analysis. In AA subjects, the region surrounding the Duffy antigen/chemokine receptor gene (DARC) on 1q21 exhibited significant association (p value = 6.71e-55). These results validate the previously reported association between WBC and of the regulatory variant rs2814778 in the promoter region, which causes the Duffy negative phenotype (Fy-/-). A second missense variant (rs12075) is responsible for the two principal antigens, Fya and Fyb of the Duffy blood group system. The two variants, consisting of four alleles, act in concert to produce five antigens and subsequent phenotypes. We were able to identify the marginal and novel interaction effects of these two variants on WBC. In the EA subjects, we identified significantly associated SNPs tagging three separate genes in the 17q21 region: (1) GSDMA, (2) MED24, and (3) PSMD3. Variants in this region have been reported to be associated with WBC, neutrophil count, and inflammatory diseases including asthma and Crohn's disease.

Original languageEnglish (US)
Pages (from-to)639-652
Number of pages14
JournalHuman Genetics
Volume131
Issue number4
DOIs
StatePublished - Apr 2012

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Electronic Health Records
Genomics
Leukocyte Count
Duffy Blood-Group System
Phenotype
Antigens
Antigen Receptors
Chemokine Receptors
Genome-Wide Association Study
Genetic Promoter Regions
Crohn Disease
Genes
Single Nucleotide Polymorphism
Patient Care
Neutrophils
Chronic Disease
Asthma
Alleles

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Crosslin, D. R., McDavid, A., Weston, N., Nelson, S. C., Zheng, X., Hart, E., ... Jarvik, G. P. (2012). Genetic variants associated with the white blood cell count in 13,923 subjects in the eMERGE Network. Human Genetics, 131(4), 639-652. https://doi.org/10.1007/s00439-011-1103-9

Genetic variants associated with the white blood cell count in 13,923 subjects in the eMERGE Network. / Crosslin, David R.; McDavid, Andrew; Weston, Noah; Nelson, Sarah C.; Zheng, Xiuwen; Hart, Eugene; De Andrade, Mariza; Kullo, Iftikhar Jan; McCarty, Catherine A.; Doheny, Kimberly F.; Pugh, Elizabeth; Kho, Abel; Hayes, M. Geoffrey; Pretel, Stephanie; Saip, Alexander; Ritchie, Marylyn D.; Crawford, Dana C.; Crane, Paul K.; Newton, Katherine; Li, Rongling; Mirel, Daniel B.; Crenshaw, Andrew; Larson, Eric B.; Carlson, Chris S.; Jarvik, Gail P.

In: Human Genetics, Vol. 131, No. 4, 04.2012, p. 639-652.

Research output: Contribution to journalArticle

Crosslin, DR, McDavid, A, Weston, N, Nelson, SC, Zheng, X, Hart, E, De Andrade, M, Kullo, IJ, McCarty, CA, Doheny, KF, Pugh, E, Kho, A, Hayes, MG, Pretel, S, Saip, A, Ritchie, MD, Crawford, DC, Crane, PK, Newton, K, Li, R, Mirel, DB, Crenshaw, A, Larson, EB, Carlson, CS & Jarvik, GP 2012, 'Genetic variants associated with the white blood cell count in 13,923 subjects in the eMERGE Network', Human Genetics, vol. 131, no. 4, pp. 639-652. https://doi.org/10.1007/s00439-011-1103-9
Crosslin, David R. ; McDavid, Andrew ; Weston, Noah ; Nelson, Sarah C. ; Zheng, Xiuwen ; Hart, Eugene ; De Andrade, Mariza ; Kullo, Iftikhar Jan ; McCarty, Catherine A. ; Doheny, Kimberly F. ; Pugh, Elizabeth ; Kho, Abel ; Hayes, M. Geoffrey ; Pretel, Stephanie ; Saip, Alexander ; Ritchie, Marylyn D. ; Crawford, Dana C. ; Crane, Paul K. ; Newton, Katherine ; Li, Rongling ; Mirel, Daniel B. ; Crenshaw, Andrew ; Larson, Eric B. ; Carlson, Chris S. ; Jarvik, Gail P. / Genetic variants associated with the white blood cell count in 13,923 subjects in the eMERGE Network. In: Human Genetics. 2012 ; Vol. 131, No. 4. pp. 639-652.
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AU - Weston, Noah

AU - Nelson, Sarah C.

AU - Zheng, Xiuwen

AU - Hart, Eugene

AU - De Andrade, Mariza

AU - Kullo, Iftikhar Jan

AU - McCarty, Catherine A.

AU - Doheny, Kimberly F.

AU - Pugh, Elizabeth

AU - Kho, Abel

AU - Hayes, M. Geoffrey

AU - Pretel, Stephanie

AU - Saip, Alexander

AU - Ritchie, Marylyn D.

AU - Crawford, Dana C.

AU - Crane, Paul K.

AU - Newton, Katherine

AU - Li, Rongling

AU - Mirel, Daniel B.

AU - Crenshaw, Andrew

AU - Larson, Eric B.

AU - Carlson, Chris S.

AU - Jarvik, Gail P.

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