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The lack of mechanistic explanations for many genotype-phenotype associations identified by GWAS precludes thorough assessment of their impact on human health. Here, we conducted an expression quantitative trait locus (eQTL) mapping analysis in erythroblasts and found erythroid-specific eQTLs for ATP2B4, the main calcium ATPase of red blood cells (rbc). The same SNPs were previously associated with mean corpuscular hemoglobin concentration (MCHC) and susceptibility to severe malaria infection. We showed that Atp2b4 / mice demonstrate increased MCHC, confirming ATP2B4 as the causal gene at this GWAS locus. Using CRISPR-Cas9, we fine mapped the genetic signal to an erythroid-specific enhancer of ATP2B4. Erythroid cells with a deletion of the ATP2B4 enhancer had abnormally high intracellular calcium levels. These results illustrate the power of combined transcriptomic, epigenomic, and genome-editing approaches in characterizing noncoding regulatory elements in phenotype-relevant cells. Our study supports ATP2B4 as a potential target for modulating rbc hydration in erythroid disorders and malaria infection. Lessard et al An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility J Clin Invest. 2017;127(8):3065 3074.
Genetics of blood-cell traits.
To analyse the blood-cell traits and test their association with genotypes using standard genetic association methodologies.
To study the genetics of these quantitative blood traits may reveal new biologic pathways that ultimately not only (1) contribute to our understanding of hematopoiesis but also (2) provide new avenues for treatment of patients with low or high blood counts, and (3) illuminate new mechanisms of association of high or low blood counts with chronic inflammatory and thrombotic diseases.
1. Samuel Lessard, et al. An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility
2. Mousas A, Ntritsos G, Chen M-H, Song C, Huffman JE, Tzoulaki I, et al. (2017). Rare coding variants pinpoint genes that control human hematological traits.