Human genetics implicates a BACH2-NRF2 axis in fetal hemoglobin activation

Human genetic studies have identified key regulators of fetal hemoglobin (HbF) expression, including BCL11A, resulting in therapeutic advances1-8. Yet the mechanisms by which HbF expression is activated remain incompletely understood9. Here, we conduct a large multi-ancestry genome-wide association study of HbF levels in 28,279 individuals that identifies 91 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 likewise increases HbF expression. Mechanistically, BACH2 restrains activation of the HbF-encoding {gamma}-globin genes, while loss of BACH2 enhances NRF2 chromatin occupancy and promotes the formation of activation foci at the {gamma}-globin genes. Although BACH2 and NRF2 binding motifs in the {gamma}-globin promoters overlap, they can be selectively edited to activate or repress {gamma}-globin, respectively, and do so independently of BCL11A. These findings illustrate how human genetic variation continues to advance our understanding of therapeutically-relevant regulatory mechanisms underlying HbF expression.