抄録
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.
元の言語 | English |
---|---|
記事番号 | e1002108 |
ジャーナル | PLoS Genetics |
巻 | 7 |
発行部数 | 6 |
DOI | |
出版物ステータス | Published - 01-06-2011 |
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All Science Journal Classification (ASJC) codes
- Ecology, Evolution, Behavior and Systematics
- Molecular Biology
- Genetics
- Genetics(clinical)
- Cancer Research
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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.
:: PLoS Genetics, 巻 7, 番号 6, e1002108, 01.06.2011.研究成果: Article
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.
UR - http://www.scopus.com/inward/record.url?scp=79959812503&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79959812503&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1002108
DO - 10.1371/journal.pgen.1002108
M3 - Article
C2 - 21738479
AN - SCOPUS:79959812503
VL - 7
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 6
M1 - e1002108
ER -