Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium

Abstract

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

Figure 1

Overview of CHARGE meta-analysis results for six erythrocyte traits: hemoglobin concentration (Hgb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), erythrocyte count (RBC). -log₁₀ (P value) is plotted on the y-axis against genomic position of each SNP. Genomic loci with significant association (P < 5 × 10^-8) are plotted in red, and loci with suggestive evidence are in blue (P < 4 × 10^-7).

Figure 2

Results of the CHARGE meta-analysis are organized into a Venn diagram, demonstrating overlap of loci meeting a genome-wide significance threshold of P < 5×10^-8.

Figure 3

Gene expression in blood and endothelial cells for genes in the chromosome 6q23.3 region. (a) SNPs in the locus are plotted against recombination rates as observed in HapMap CEU, using a window of +/-500kb around the lead SNP identified in this locus, which is plotted in blue. SNPs identified by the CHARGE meta-analyses are colored according to correlation with the lead SNP (r² ≥ 0.8 red; 0.5 ≤ r² < 0.8 orange; 0.2 ≤ r² < 0.5 yellow; r² < 0.2 white; no r² value provided). The P value for the lead SNP in this region is provided. (b) A heatmap of gene expression levels in nine blood and endothelial cell lines is shown, including all genes, as annotated by ENSEMBL 54, within the +/- 500kb window of the locus (MK = megakaryocyte; EB = erythroid bodies; HUVEC = human umbilical vein endothelial cells; CD14 = monocytes; CD66b = granulocytes; CD19 = B lymphocytes; CD56 = NK cells; CD8 = Tc lymphocytes; CD4 = Th lymphocytes).