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Meta-Analysis
. 2011 Jun;7(6):e1002108.
doi: 10.1371/journal.pgen.1002108. Epub 2011 Jun 30.

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  1 , 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 Kubo, Andrea LaCroix, Leslie A Lange, Simin Liu, Kurt Lohman, Yan Meng, Emile R Mohler 3rd, 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 Jr, 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
Affiliations
Meta-Analysis

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 et al. PLoS Genet. 2011 Jun.

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Quantile–quantile plot of P-values in meta-analysis for total white blood count.
Panel A includes all markers, panel B excludes markers on chromosome 1. Horizontal axis indicates expected −log10 P-values. Vertical axis indicates observed −log10 P-values. The red line represents y = x. The marked deviation from expectations in panel A is due to markers on chromosome 1 near the DARC locus. The individual study ancestry-corrected inflation factors with (without) chromosome 1 markers were 1.06 (1.04) for ARIC, 1.02 (1.01) for CARDIA, 1.11 (1.08) for JHS, 1.03 (1.01) for Health ABC, 1.09 (1.05) for WHI, 1.04 (1.00) for GeneSTAR, and 1.01 (0.98) for HANDLS. The overall inflation factor prior to correction was 1.05 (0.98).
Figure 2
Figure 2. Manhattan plot of meta-analysis P-values in GWAS for total WBC count.
Horizontal axis indicates chromosomal position. Vertical axis indicates −log10 P-values from inverse variance-weighted fixed effects meta-analysis. The red horizontal line indicates the genome-wide significance threshold of P = 2.5×10−8. Association signals are present at 1q23, 4q13, and 16q22. The P-values for the broad chromosome 1 signal are truncated at 10−20. This region spans nearly 90 Mb on both arms of chromosome 1 and results artifactually in two apparently distinct peaks because of the lack of genotyped or imputed SNPs around the centromere.
Figure 3
Figure 3. Population-specific −log P values for total WBC association at the chromosome 4q13 CXCL2 locus.
Shown is a 500 kb window of chromosome 4q13 centered at rs9131 (purple square). Plots were generated for African Americans (top panel), European Americans (middle panel), Japanese (bottom panel), using LocusZoom. The color of each SNP indicates the level of pairwise linkage disequilibrium (r-squared) relative to the index SNP rs9131. R-squared values were calculated from HapMap (release 22) YRI (top panel), CEU (middle panel), or CHB+JPT (bottom panel) populations. SNPs with missing LD information are shown in grey.
Figure 4
Figure 4. Trans-population meta-analysis results for total WBC count at the chromosome 4q13 CXCL2 locus.
The strongest association signal is localized to an LD bin of several SNPs within the CXCL2 promoter and 5′ flanking region, including rs1371799 (purple triangle). Meta-analysis was performed using Fisher's method to combine P-values across African, European, and Japanese populations. The 99% confidence interval for the cross-population association signal mapped to a 75 kb region shaded in light blue (lower panel). Plot was generated using LocusZoom. Linkage disequilibrium is shown for the African population.
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