Admixture Mapping of White Cell Count: Genetic Locus Responsible for Lower White Blood Cell Count in the Health ABC and Jackson Heart Studies

Abstract

White blood cell count (WBC) is an important clinical marker that varies among different ethnic groups. African Americans are known to have a lower WBC than European Americans. We surveyed the entire genome for loci underlying this difference in WBC by using admixture mapping. We analyzed data from African American participants in the Health, Aging, and Body Composition Study and the Jackson Heart Study. Participants of both studies were genotyped across >or= 1322 single nucleotide polymorphisms that were pre-selected to be informative for African versus European ancestry and span the entire genome. We used these markers to estimate genetic ancestry in each chromosomal region and then tested the association between WBC and genetic ancestry at each locus. We found a locus on chromosome 1q strongly associated with WBC (p < 10(-12)). The strongest association was with a marker known to affect the expression of the Duffy blood group antigen. Participants who had both copies of the common West African allele had a mean WBC of 4.9 (SD 1.3); participants who had both common European alleles had a mean WBC of 7.1 (SD 1.3). This variant explained approximately 20% of population variation in WBC. We used admixture mapping, a novel method for conducting genetic-association studies, to find a region that was significantly associated with WBC on chromosome 1q. Additional studies are needed to determine the biological mechanism for this effect and its clinical implications.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

“…Lineage commitment of hematopoietic stem cells involves precise transcriptional and epigenetic regulation, creating the WBC traits in European ancestry populations 6 and less than 25% in African ancestry (AA) populations (in AA, a substantial proportion of the variation in WBC counts is attributed to a single variant-rs2814778-in DARC [Duffy Antigen Receptor for Chemokines (MIM: 613665)]). 3,13 In an effort to augment the discoveries from GWASs and to identify additional functional loci contributing to variation in WBC counts, we performed exome array-based meta-analysis of total and differential counts in a multiancestry samples from 25 studies.…”

A pilot study to determine the normal haematological indices for young Malawian adults in Blantyre, Malawi

“…23 Research indicates that total WBC and neutrophil counts are lower among individuals of African descent because of the common African-derived ''null'' variant (rs2814778) of the Duffy antigen receptor for chemokines (DARC) gene. [24][25][26] It has been shown that by stopping the expression of DARC on RBCs, the Duffy null variant may alter the concentration and distribution of chemokines in the blood and tissue, [27][28][29][30] thus regulating neutrophil production and migration. This could be another reason for the low WBC counts among the apparently normal Malawian blood donors.…”

Organization, Variation and Expression of the Human Genome

“…First is the use of admixture mapping, tracing the location of particular SNPs associated with disease in populations of patients whose genomes are a mixture from at least two original populations, for example, African-Americans or Latinos (Price et al, 2007;Smith et al, 2004). Such an approach has already been used to map genes associated with several phenotypes whose frequency differs markedly between different population groups, including prostate cancer (Freedman et al, 2006), hypertension (Deo et al, 2007), skin pigmentation (McEvoy et al, 2006) and white blood cell count (Nalls et al, 2008).…”