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 J. 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 Li; Daniel B. Mirel; Andrew Crenshaw; Eric B. Larson; Chris S. Carlson; Gail P. Jarvik

doi:10.1007/s00439-011-1103-9

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 J. 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 language	English (US)
Pages (from-to)	639-652
Number of pages	14
Journal	Human Genetics
Volume	131
Issue number	4
DOIs	https://doi.org/10.1007/s00439-011-1103-9
State	Published - Apr 2012

Bibliographical note

Funding Information:
Acknowledgments The authors are grateful to all the participants in the eMERGE study. They also acknowledge Xiuwen Zheng and the fast PCA program to make principal component analysis on this many subjects achievable. This study was supported by the following U01 grants from the National Human Genome Research Institute (NHGRI), a component of the National Institutes of Health (NIH), Bethesda, MD, USA: (1) HG004610, AG06781 (Group Health Cooperative), (2) HG04599 (Mayo Clinic), (3) HG004608 (Marsh-field Clinic), (4) HG004609 (Northwestern University), (5) HG004438 (CIDR), (6) HG004424 (BROAD), and (7) HG004603 (Vanderbilt University). Additional support was provided by the University of Washington’s Northwest Institute of Genetic Medicine from Washington State Life Sciences Discovery funds (Grant 265508).

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Crosslin, D. R., McDavid, A., Weston, N., Nelson, S. C., Zheng, X., Hart, E., De Andrade, M., Kullo, I. J., McCarty, C. A., Doheny, K. F., Pugh, E., Kho, A., Hayes, M. G., Pretel, S., Saip, A., Ritchie, M. D., Crawford, D. C., Crane, P. K., Newton, K., ... 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

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

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

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.",

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

note = "Funding Information: Acknowledgments The authors are grateful to all the participants in the eMERGE study. They also acknowledge Xiuwen Zheng and the fast PCA program to make principal component analysis on this many subjects achievable. This study was supported by the following U01 grants from the National Human Genome Research Institute (NHGRI), a component of the National Institutes of Health (NIH), Bethesda, MD, USA: (1) HG004610, AG06781 (Group Health Cooperative), (2) HG04599 (Mayo Clinic), (3) HG004608 (Marsh-field Clinic), (4) HG004609 (Northwestern University), (5) HG004438 (CIDR), (6) HG004424 (BROAD), and (7) HG004603 (Vanderbilt University). Additional support was provided by the University of Washington{\textquoteright}s Northwest Institute of Genetic Medicine from Washington State Life Sciences Discovery funds (Grant 265508).",

year = "2012",

month = apr,

doi = "10.1007/s00439-011-1103-9",

language = "English (US)",

volume = "131",

pages = "639--652",

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T1 - Genetic variants associated with the white blood cell count in 13,923 subjects in the eMERGE Network

AU - Crosslin, David R.

AU - McDavid, Andrew

AU - Weston, Noah

AU - Nelson, Sarah C.

AU - Zheng, Xiuwen

AU - Hart, Eugene

AU - De Andrade, Mariza

AU - Kullo, Iftikhar J.

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.

N1 - Funding Information: Acknowledgments The authors are grateful to all the participants in the eMERGE study. They also acknowledge Xiuwen Zheng and the fast PCA program to make principal component analysis on this many subjects achievable. This study was supported by the following U01 grants from the National Human Genome Research Institute (NHGRI), a component of the National Institutes of Health (NIH), Bethesda, MD, USA: (1) HG004610, AG06781 (Group Health Cooperative), (2) HG04599 (Mayo Clinic), (3) HG004608 (Marsh-field Clinic), (4) HG004609 (Northwestern University), (5) HG004438 (CIDR), (6) HG004424 (BROAD), and (7) HG004603 (Vanderbilt University). Additional support was provided by the University of Washington’s Northwest Institute of Genetic Medicine from Washington State Life Sciences Discovery funds (Grant 265508).

PY - 2012/4

Y1 - 2012/4

N2 - 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.

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

Abstract

Bibliographical note

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