Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10^−5), establishing a novel phenotype for this genetic variant

Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10−5), establishing a novel phenotype for this genetic variant

Enhanced Statistical Tests for GWAS in Admixed Populations: Assessment using African Americans from CARe and a Breast Cancer Consortium

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations

Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene.

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8 x 10(-5)), establishing a novel phenotype for this genetic variant

Ancestry analysis of BAC clones that are the source of the human genome reference sequence across the chromosome 1 locus.

<p>The human genome reference sequence across the admixture peak is pieced together from 5 BAC clones, which turn out to be a mosaic of European and African ancestry. To determine ancestry, we examined the haplotype of the human genome reference sequence for 284 SNPs for which data are available from the International Haplotype Map Project, and then output the ratio of the number of perfect matches to the reference sequence haplotype in 120 European American to the number of perfect matches in 120 West African chromosomes (conservatively adding 1 to the counts). Values above 10 indicate strong (>10∶1) evidence for a European haplotype, and values below 0.1 indicate strong (<1∶10) evidence for an African haplotype. RPCI-11, the individual who is the source of ∼74% of the human genome reference sequence, has two clones of entirely African and two clones of entirely European ancestry at this locus, strongly indicating that the human genome reference sequence is primarily that of an African American. We included these BAC clones in our search for polymorphisms across the admixture peak that were consistent with being fixed in frequency between European and African populations.</p

Effect of the chromosome 1 locus on white blood cell counts.

*<p>European ancestry at the locus has an essentially dominant effect on white blood cell counts. None of the differential counts phenotypes shows a significant difference between the 1,647 <i>FY</i>−/<i>FY</i>+ heterozygotes and 247 <i>FY</i>+/<i>FY</i>+ homozygotes after correcting for 7 hypotheses tested (Bonferroni corrected P = 0.48). However, all white blood cell counts except bands show significant associations comparing the 4,111 <i>FY</i>−/<i>FY</i>− homozygotes to the 1,894 carriers of the <i>FY</i>+ allele (Z-scores between 4.2 and 49.7 standard deviations).</p>†<p>After controlling for neutrophil level, there is weak additional evidence for association to the chromosome 1 locus only for monocytes and basophils. For subsequent mapping analyses we only focused on neutrophil levels, as adding these other residuals did not substantially increase the strength of the association. We do not estimate correlation coefficients of the associations that are not significant.</p

Admixture association defines a 451 kb region containing the risk allele.

<p>The LOD score for admixture association to neutrophil count shows a peak of 363.1, and a 99% confidence interval of 155.957–156.408 Mb (the region where the LOD score is within 1.44 of its maximum). The known genes under the peak are obtained using a screenshot of the “Known Genes” track from the UCSC genome browser (<a href="http://genome.ucsc.edu" target="_blank">http://genome.ucsc.edu</a>).</p

Comparison of phenotypic characteristics for the four sets of samples used in this study.

<p>Note: For the differential white blood cell counts, we present absolute values, obtained by multiplying the differential counts (expressed as a percentage of total WBC) by the total WBC. The Health ABC study did not obtain band counts.</p>*<p>For the JHS-ARIC overlap samples, the values of all phenotypes (age, BMI, and differential white blood cell counts) are averaged between the JHS and ARIC baseline measurements, taken an average of 14 years apart. Analyses in all other groups use a single measurement at the cohort baseline.</p>§<p>Average percentage of European ancestry was estimated using the ANCESTRYMAP software. European ancestry “carrier status” was defined by rs2814778 genotype.</p>†<p>Neutrophil count is used to assess the genetic association, since it accounts for essentially all the correlation to the chromosome 1 locus and thus provides the best measure of association (text and <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000360#pgen-1000360-t002" target="_blank">Table 2</a>). Association analyses are carried out on the normally transformed rank-ordered values of the absolute neutrophil count. Standard errors on the correlation coefficients are obtained by a leave-1-out jackknife analysis.</p

Stratification of samples into 12 groups for admixture mapping analysis.

<p>Stratification of samples into 12 groups for admixture mapping analysis.</p