Human genetic variation has enabled the identification of several key regulators of fetal-to-adult hemoglobin switching, including BCL11A, resulting in therapeutic advances. However, despite the progress made, limited further insights have been obtained to provide a fuller accounting of how genetic variation contributes to the global mechanisms of fetal hemoglobin (HbF) gene regulation. Here, we have conducted a multi-ancestry genome-wide association study of 28,279 individuals from several cohorts spanning 5 continents to define the architecture of human genetic variation impacting HbF. We have identified a total of 178 conditionally independent genome-wide significant or suggestive variants across 14 genomic windows. Importantly, these new data enable us to better define the mechanisms by which HbF switching occurs in vivo. We conduct targeted perturbations to define BACH2 as a new genetically-nominated regulator of hemoglobin switching. We define putative causal variants and underlying mechanisms at the well-studied BCL11A and HBS1L-MYB loci, illuminating the complex variant-driven regulation present at these loci. We additionally show how rare large-effect deletions in the HBB locus can interact with polygenic variation to influence HbF levels. Our study paves the way for the next generation of therapies to more effectively induce HbF in sickle cell disease and β-thalassemia.

During the drafting of the manuscript, D.S.P. became a full-time employee of AstraZeneca. F.A. is an employee and shareholder of Illumina, Inc. M.T.G. serves as a consultant for Actelion, Bayer Healthcare, Pfizer, Forma, and Fulcrum Therapeutics. A.H.L. reports speakers honoraria from Siemens Healthineers and Beckman Diagnostics, as well as participation on an advisory board of Roche Diagnostics, all unrelated to the present work. K.S., G.T. and U.T. are employed by deCODE Genetics/Amgen Inc. A.S.B. reports institutional grants from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Novartis, Regeneron and Sanofi. V.G.S. serves as an advisor to and/or has equity in Branch Biosciences, Ensoma, Novartis, Forma, and Cellarity, all unrelated to the present work.

This work was supported by the New York Stem Cell Foundation (to V.G.S), NIH grants R01 DK103794 and R01 HL146500 (to V.G.S). V.G.S is a New York Stem Cell Robertson Investigator.

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