Genetic regulation of fetal hemoglobin across global populations

Human genetic studies have identified key regulators of fetal hemoglobin (HbF) expression, including BCL11A, resulting in therapeutic advances. Yet the mechanisms by which HbF expression is activated remain incompletely understood. Here, we conduct a multi-ancestry genome-wide association study of HbF levels in 28,237 individuals that identifies 131 conditionally-independent associations across 12 genomic regions. In one previously uncharacterized associated region, the high-HbF-linked causal variant, rs1010474-C, reduces BACH2 expression and elevates HbF levels. Direct perturbation or inhibition of BACH2 elevates HbF expression. Mechanistically, BACH2 restrains activation of the HbF-encoding{gamma} -globin genes, while loss of BACH2 enhances NRF2 chromatin occupancy and promotes activation foci formation at the{gamma} -globin genes. BACH2 and NRF2 binding motifs in the{gamma} -globin promoters, while overlapping, can be selectively edited to activate or repress{gamma} -globin, respectively, and function independently of BCL11A. These findings illustrate how human genetic variation continues to advance our knowledge of therapeutically-relevant regulatory mechanisms underlying HbF expression.