Lessard, SamuelGatof, Emily SternBeaudoin, MélissaSchupp, Patrick G.Sher, FalakAli, AdnanPrehar, SukhpalKurita, RyoNakamura, YukioBaena, EstherLedoux, JonathanOceandy, DelvacBauer, Daniel E.Lettre, Guillaume2025-12-162025-12-160021-9738PubMed:28714864ORCID:/0000-0002-8344-3776/work/167651701https://hdl.handle.net/1885/733795230The 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.Part of this research has been conducted using the UKBB resource under application number 11707. The authors wish to thank Gerald Lilly and Louis R. Villeneuve for assistance and Seth L. Alper, Carlo Brugnara, and Elizabeth Egan for comments. SL holds fellowships from the Canadian Institute of Health Research (CIHR) and the "Fondation Pierre Lavoie." ESG was the recipient of an American Society of Hematology HONORS award. AA holds a Cancer Research UK Clinical Training Award (C147/A19496). EB is supported by a Cancer Research UK start-up grant (C5759/A20971). DO was supported by a British Heart Foundation Intermediate Fellowship (FS/09/046/28043) and British Heart Foundation project grants (PG/13/12/30017 and PG/16/77/32400). DEB was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K08DK093705, R03DK109232), the National Heart, Lung, and Blood Institute (DP2OD022716), the Burroughs Wellcome Fund, the American Society of Hematology, and the Doris Duke Charitable, Charles H. Hood, and Cooley's Anemia foundations. GL was supported by grants from the CIHR (no. 123382), the Doris Duke Charitable Foundation, the National Sciences and Engineering Research Council of Canada (RGPIN-2016-04597), the Montreal Heart Institute Foundation, and the Canada Research Chair Program.10en2017-08-0110.1172/JCI9437885026641823