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

Yet the mechanisms by which HbF expression is activated remain incompletely understood7. Here, we conduct a large multi-ancestry genome-wide association study of HbF levels in 28,278 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 -globin genes, while loss of BACH2 enhances NRF2 chromatin occupancy and promotes the formation of activation foci at the -globin genes.