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.
authors: Department of Epidemiology, University of Washington, Seattle, Washington, United States of America. apreiner@u.washington.edu
authors: Alexander P
authors: AP
authors: Reiner
authors: Guillaume
authors: G
authors: Lettre
authors: Michael A
authors: MA
authors: Nalls
authors: Santhi K
authors: SK
authors: Ganesh
authors: Rasika
authors: R
authors: Mathias
authors: Melissa A
authors: MA
authors: Austin
authors: Eric
authors: E
authors: Dean
authors: Sampath
authors: S
authors: Arepalli
authors: Angela
authors: A
authors: Britton
authors: Zhao
authors: Z
authors: Chen
authors: David
authors: D
authors: Couper
authors: J David
authors: JD
authors: Curb
authors: Charles B
authors: CB
authors: Eaton
authors: Myriam
authors: M
authors: Fornage
authors: Struan F A
authors: SF
authors: Grant
authors: Tamara B
authors: TB
authors: Harris
authors: Dena
authors: D
authors: Hernandez
authors: Naoyuki
authors: N
authors: Kamatini
authors: Brendan J
authors: BJ
authors: Keating
authors: Michiaki
authors: M
authors: Kubo
authors: Andrea
authors: A
authors: LaCroix
authors: Leslie A
authors: LA
authors: Lange
authors: Simin
authors: S
authors: Liu
authors: Kurt
authors: K
authors: Lohman
authors: Yan
authors: Y
authors: Meng
authors: Emile R
authors: ER
authors: Mohler
authors: Solomon
authors: S
authors: Musani
authors: Yusuke
authors: Y
authors: Nakamura
authors: Christopher J
authors: CJ
authors: O'Donnell
authors: Yukinori
authors: Y
authors: Okada
authors: Cameron D
authors: CD
authors: Palmer
authors: George J
authors: GJ
authors: Papanicolaou
authors: Kushang V
authors: KV
authors: Patel
authors: Andrew B
authors: AB
authors: Singleton
authors: Atsushi
authors: A
authors: Takahashi
authors: Hua
authors: H
authors: Tang
authors: Herman A
authors: HA
authors: Taylor
authors: Kent
authors: K
authors: Taylor
authors: Cynthia
authors: C
authors: Thomson
authors: Lisa R
authors: LR
authors: Yanek
authors: Lingyao
authors: L
authors: Yang
authors: Elad
authors: E
authors: Ziv
authors: Alan B
authors: AB
authors: Zonderman
authors: Aaron R
authors: AR
authors: Folsom
authors: Michele K
authors: MK
authors: Evans
authors: Yongmei
authors: Y
authors: Liu
authors: Diane M
authors: DM
authors: Becker
authors: Beverly M
authors: BM
authors: Snively
authors: James G
authors: JG
authors: Wilson
mesh_terms: D001741:Black or African American / Q000235:genetics*; D016477:Artifacts; D044466:Asian People / Q000235:genetics; D054426:Chemokine CXCL2 / Q000235:genetics; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D004375:Duffy Blood-Group System / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007958:Leukocyte Count; D008840:Microfilament Proteins / Q000235:genetics; D017720:Molecular Epidemiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics; D015203:Reproducibility of Results; D044465:White People / Q000235:genetics
chemical_list: C473745:ACKR1 protein, human; C499706:CXCL2 protein, human; D054426:Chemokine CXCL2; D004375:Duffy Blood-Group System; D008840:Microfilament Proteins; D011956:Receptors, Cell Surface