Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network

Abstract

Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ~16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.

Figure 1.

Manhattan plots of GWAS analysis for RBC traits (A) Hct; (B) Hgb; (C) MCHC; (D) MCH; (E) MCV; (F) RBC count and (G) RDW. The dashed horizontal red line indicates P = 1 × 10⁻⁸. The dashed horizontal blue line indicates P = 5 × 10⁻³.

Figure 2.

Admixture scan of Hgb concentration. (A) shows a genome-wide plot of −log(P-values) for local-ancestry association with Hgb. The dashed horizontal line indicates the experiment-wide admixture scan significance threshold of P < 7 × 10⁻⁶. (B) indicates a zoom-in of the genome-wide significant region on chromosome 6, where there appears to be a broad, bimodal admixture peak. The region corresponding to the HFE gene is shown in blue.