Genome-Wide association study of white blood cell count in 16,388 african americans: The continental Origins and Genetic Epidemiology network (COGENT)

Alexander P. Reiner, Guillaume Lettre, Michael A. Nalls, Santhi K. Ganesh, Rasika Mathias, Melissa A. Austin, Eric Dean, Sampath Arepalli, Angela Britton, Zhao Chen, David Couper, J. David Curb, Charles B. Eaton, Myriam Fornage, Struan F.A. Grant, Tamara B. Harris, Dena Hernandez, Naoyuki Kamatini, Brendan J. Keating, Michiaki KuboAndrea LaCroix, Leslie A. Lange, Simin Liu, Kurt Lohman, Yan Meng, Emile R. Mohler, Solomon Musani, Yusuke Nakamura, Christopher J. O'Donnell, Yukinori Okada, Cameron D. Palmer, George J. Papanicolaou, Kushang V. Patel, Andrew B. Singleton, Atsushi Takahashi, Hua Tang, Herman A. Taylor, Kent Taylor, Cynthia Thomson, Lisa R. Yanek, Lingyao Yang, Elad Ziv, Alan B. Zonderman, Aaron R. Folsom, Michele K. Evans, Yongmei Liu, Diane M. Becker, Beverly M. Snively, James G. Wilson

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived "null" variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10-8). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS.

Original languageEnglish
Article numbere1002108
JournalPLoS Genetics
Volume7
Issue number6
DOIs
Publication statusPublished - 01-06-2011

Fingerprint

Molecular Epidemiology
African American
Genome-Wide Association Study
African Americans
epidemiology
Leukocyte Count
leukocyte count
leukocytes
genome
Chromosomes
blood
Leukocytes
chromosome
chromosomes
Chemokines
Chromosome Duplication
Antigen Receptors
Population
loci
Single Nucleotide Polymorphism

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Reiner, Alexander P. ; Lettre, Guillaume ; Nalls, Michael A. ; Ganesh, Santhi K. ; Mathias, Rasika ; Austin, Melissa A. ; Dean, Eric ; Arepalli, Sampath ; Britton, Angela ; Chen, Zhao ; Couper, David ; Curb, J. David ; Eaton, Charles B. ; Fornage, Myriam ; Grant, Struan F.A. ; Harris, Tamara B. ; Hernandez, Dena ; Kamatini, Naoyuki ; Keating, Brendan J. ; Kubo, Michiaki ; LaCroix, Andrea ; Lange, Leslie A. ; Liu, Simin ; Lohman, Kurt ; Meng, Yan ; Mohler, Emile R. ; Musani, Solomon ; Nakamura, Yusuke ; O'Donnell, Christopher J. ; Okada, Yukinori ; Palmer, Cameron D. ; Papanicolaou, George J. ; Patel, Kushang V. ; Singleton, Andrew B. ; Takahashi, Atsushi ; Tang, Hua ; Taylor, Herman A. ; Taylor, Kent ; Thomson, Cynthia ; Yanek, Lisa R. ; Yang, Lingyao ; Ziv, Elad ; Zonderman, Alan B. ; Folsom, Aaron R. ; Evans, Michele K. ; Liu, Yongmei ; Becker, Diane M. ; Snively, Beverly M. ; Wilson, James G. / Genome-Wide association study of white blood cell count in 16,388 african americans : The continental Origins and Genetic Epidemiology network (COGENT). In: PLoS Genetics. 2011 ; Vol. 7, No. 6.
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title = "Genome-Wide association study of white blood cell count in 16,388 african americans: The continental Origins and Genetic Epidemiology network (COGENT)",
abstract = "Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived {"}null{"} variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10-8). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS.",
author = "Reiner, {Alexander P.} and Guillaume Lettre and Nalls, {Michael A.} and Ganesh, {Santhi K.} and Rasika Mathias and Austin, {Melissa A.} and Eric Dean and Sampath Arepalli and Angela Britton and Zhao Chen and David Couper and Curb, {J. David} and Eaton, {Charles B.} and Myriam Fornage and Grant, {Struan F.A.} and Harris, {Tamara B.} and Dena Hernandez and Naoyuki Kamatini and Keating, {Brendan J.} and Michiaki Kubo and Andrea LaCroix and Lange, {Leslie A.} and Simin Liu and Kurt Lohman and Yan Meng and Mohler, {Emile R.} and Solomon Musani and Yusuke Nakamura and O'Donnell, {Christopher J.} and Yukinori Okada and Palmer, {Cameron D.} and Papanicolaou, {George J.} and Patel, {Kushang V.} and Singleton, {Andrew B.} and Atsushi Takahashi and Hua Tang and Taylor, {Herman A.} and Kent Taylor and Cynthia Thomson and Yanek, {Lisa R.} and Lingyao Yang and Elad Ziv and Zonderman, {Alan B.} and Folsom, {Aaron R.} and Evans, {Michele K.} and Yongmei Liu and Becker, {Diane M.} and Snively, {Beverly M.} and Wilson, {James G.}",
year = "2011",
month = "6",
day = "1",
doi = "10.1371/journal.pgen.1002108",
language = "English",
volume = "7",
journal = "PLoS Genetics",
issn = "1553-7390",
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Reiner, AP, Lettre, G, Nalls, MA, Ganesh, SK, Mathias, R, Austin, MA, Dean, E, Arepalli, S, Britton, A, Chen, Z, Couper, D, Curb, JD, Eaton, CB, Fornage, M, Grant, SFA, Harris, TB, Hernandez, D, Kamatini, N, Keating, BJ, Kubo, M, LaCroix, A, Lange, LA, Liu, S, Lohman, K, Meng, Y, Mohler, ER, Musani, S, Nakamura, Y, O'Donnell, CJ, Okada, Y, Palmer, CD, Papanicolaou, GJ, Patel, KV, Singleton, AB, Takahashi, A, Tang, H, Taylor, HA, Taylor, K, Thomson, C, Yanek, LR, Yang, L, Ziv, E, Zonderman, AB, Folsom, AR, Evans, MK, Liu, Y, Becker, DM, Snively, BM & Wilson, JG 2011, 'Genome-Wide association study of white blood cell count in 16,388 african americans: The continental Origins and Genetic Epidemiology network (COGENT)', PLoS Genetics, vol. 7, no. 6, e1002108. https://doi.org/10.1371/journal.pgen.1002108

Genome-Wide association study of white blood cell count in 16,388 african americans : The continental Origins and Genetic Epidemiology network (COGENT). / Reiner, Alexander P.; Lettre, Guillaume; Nalls, Michael A.; Ganesh, Santhi K.; Mathias, Rasika; Austin, Melissa A.; Dean, Eric; Arepalli, Sampath; Britton, Angela; Chen, Zhao; Couper, David; Curb, J. David; Eaton, Charles B.; Fornage, Myriam; Grant, Struan F.A.; Harris, Tamara B.; Hernandez, Dena; Kamatini, Naoyuki; Keating, Brendan J.; Kubo, Michiaki; LaCroix, Andrea; Lange, Leslie A.; Liu, Simin; Lohman, Kurt; Meng, Yan; Mohler, Emile R.; Musani, Solomon; Nakamura, Yusuke; O'Donnell, Christopher J.; Okada, Yukinori; Palmer, Cameron D.; Papanicolaou, George J.; Patel, Kushang V.; Singleton, Andrew B.; Takahashi, Atsushi; Tang, Hua; Taylor, Herman A.; Taylor, Kent; Thomson, Cynthia; Yanek, Lisa R.; Yang, Lingyao; Ziv, Elad; Zonderman, Alan B.; Folsom, Aaron R.; Evans, Michele K.; Liu, Yongmei; Becker, Diane M.; Snively, Beverly M.; Wilson, James G.

In: PLoS Genetics, Vol. 7, No. 6, e1002108, 01.06.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-Wide association study of white blood cell count in 16,388 african americans

T2 - The continental Origins and Genetic Epidemiology network (COGENT)

AU - Reiner, Alexander P.

AU - Lettre, Guillaume

AU - Nalls, Michael A.

AU - Ganesh, Santhi K.

AU - Mathias, Rasika

AU - Austin, Melissa A.

AU - Dean, Eric

AU - Arepalli, Sampath

AU - Britton, Angela

AU - Chen, Zhao

AU - Couper, David

AU - Curb, J. David

AU - Eaton, Charles B.

AU - Fornage, Myriam

AU - Grant, Struan F.A.

AU - Harris, Tamara B.

AU - Hernandez, Dena

AU - Kamatini, Naoyuki

AU - Keating, Brendan J.

AU - Kubo, Michiaki

AU - LaCroix, Andrea

AU - Lange, Leslie A.

AU - Liu, Simin

AU - Lohman, Kurt

AU - Meng, Yan

AU - Mohler, Emile R.

AU - Musani, Solomon

AU - Nakamura, Yusuke

AU - O'Donnell, Christopher J.

AU - Okada, Yukinori

AU - Palmer, Cameron D.

AU - Papanicolaou, George J.

AU - Patel, Kushang V.

AU - Singleton, Andrew B.

AU - Takahashi, Atsushi

AU - Tang, Hua

AU - Taylor, Herman A.

AU - Taylor, Kent

AU - Thomson, Cynthia

AU - Yanek, Lisa R.

AU - Yang, Lingyao

AU - Ziv, Elad

AU - Zonderman, Alan B.

AU - Folsom, Aaron R.

AU - Evans, Michele K.

AU - Liu, Yongmei

AU - Becker, Diane M.

AU - Snively, Beverly M.

AU - Wilson, James G.

PY - 2011/6/1

Y1 - 2011/6/1

N2 - Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived "null" variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10-8). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS.

AB - Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived "null" variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10-8). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS.

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U2 - 10.1371/journal.pgen.1002108

DO - 10.1371/journal.pgen.1002108

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