Sequence variants in three loci influence monocyte counts and erythrocyte volume

Abstract

Blood cells participate in vital physiological processes, and their numbers are tightly regulated so that homeostasis is maintained. Disruption of key regulatory mechanisms underlies many blood-related Mendelian diseases but also contributes to more common disorders, including atherosclerosis. We searched for quantitative trait loci (QTL) for hematology traits through a whole-genome association study, because these could provide new insights into both hemopoeitic and disease mechanisms. We tested 1.8 million variants for association with 13 hematology traits measured in 6015 individuals from the Australian and Dutch populations. These traits included hemoglobin composition, platelet counts, and red blood cell and white blood cell indices. We identified three regions of strong association that, to our knowledge, have not been previously reported in the literature. The first was located in an intergenic region of chromosome 9q31 near LPAR1, explaining 1.5% of the variation in monocyte counts (best SNP rs7023923, p=8.9x10(-14)). The second locus was located on chromosome 6p21 and associated with mean cell erythrocyte volume (rs12661667, p=1.2x10(-9), 0.7% variance explained) in a region that spanned five genes, including CCND3, a member of the D-cyclin gene family that is involved in hematopoietic stem cell expansion. The third region was also associated with erythrocyte volume and was located in an intergenic region on chromosome 6q24 (rs592423, p=5.3x10(-9), 0.6% variance explained). All three loci replicated in an independent panel of 1543 individuals (p values=0.001, 9.9x10(-5), and 7x10(-5), respectively). The identification of these QTL provides new opportunities for furthering our understanding of the mechanisms regulating hemopoietic cell fate.

Figure 1

Main Association Results (A–C) Regional association plots for three previously unpublished loci associated with peripheral-blood monocyte counts (A) and mean cell erythrocyte volume (MCV; B and C). The most-associated SNP for each region is shown in blue, and the color of the remaining markers reflects the linkage disequilibrium (r²) with the top SNP in each panel (increasing red hue associated with increasing r²). The recombination rate (second y axis) is plotted in light blue and is based on the CEU HapMap population. Exons for each gene are represented by vertical bars, based on all isoforms available from the March 2006 UCSC Genome Browser assembly. (D) Mean MCV volume (main y axis) as a function of the number of high-MCV alleles at five confirmed MCV loci: 6p21 (rs12661667), 6q24 (rs592423), HBS1L/MYB (rs11154792), TMPRSS6 (rs4820268), and HFE (rs1408272). The gray curve represents the population frequency (second y axis) of the ten observed cumulative allele categories. Vertical bars correspond to the 95% confidence interval around the mean.