WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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
The proliferation and differentiation of hematopoietic progenitor cells into mature blood cells is a tightly regulated process. Red blood cell (RBC), white blood cell (WBC) and platelet counts are used in medicine as biomarkers to monitor general health status, to diagnose diseases, and as prognostic indicators of various clinical disorders. The goals of our study are: (1) to identify novel genetic variants associated with blood-cell trait variation in the UK Biobank participants and (2) test if these genetic variants also associate with cardiovascular diseases, including stroke. Variation in blood-cell traits is observed in various human diseases (e.g. cancer) and is used as predictive marker for heart diseases and stroke. Our project will explore the genetic contribution to inter-individual blood-cell variation, and test whether these genetic factors also influence our risk of heart diseases and stroke. The number and features of the main blood cells (red blood cells, white blood cells, and platelets) have been measured in all UK Biobank participants. Similarly, the DNA of all UK Biobank participants will be genotyped on the UK Biobank Affymetrix array. We propose to test the correlation between genotypes and inter-individual variation in blood-cell traits using standard genetic association methodologies. When appropriate, we will control blood-cell variables with potential confounders (such as sex, age, cancer status, infectious disease status, kidney or liver disease, etc.). Full cohort.