An African ancestry-enriched H1 sub-haplotype challenges MAPT haplotype assignment and reveals distinct tau regulatory programs.

The 17q21.31 inversion locus is among the strongest genetic modifiers of tau-related neurodegenerative disease, yet its structure and function across ancestries remain incompletely understood. By integrating long-read sequencing, transcriptomics from postmortem human brain tissue, induced pluripotent stem cell (iPSC)-derived neurons, and astrocytes, we identified H1_A, a previously unrecognized non-inverted H1 sub-haplotype enriched in individuals of African ancestry (AA). H1_A carries rs8070723, a variant widely used to define the protective H2 haplotype, revealing the limitations of current MAPT haplotype assignment in non-European populations. Across brain tissue and neural cell types, ancestry and haplotype influenced MAPT expression, tau isoform composition, extracellular matrix pathways, immune signaling, and oxidative stress responses. Functional studies further demonstrated effects on astrocyte migration and glutathione regulation. These findings uncover ancestry-dependent regulatory programs at 17q21.31 and provide a framework for more accurate interpretation of MAPT-associated risk in neurodegenerative disease.