MAPT Subhaplotypes in Different Progressive Supranuclear Palsy Phenotypes

TL;DR

This study explores how different genetic variations in the MAPT gene affect the risk of developing Progressive Supranuclear Palsy (PSP) in a Southern Italian population.

Contribution

The study identifies 18 MAPT H1 subhaplotypes and highlights the protective role of the H1j subhaplotype against PSP.

Findings

H1 haplotype increases the risk of PSP (OR, 2.620), while H2 is protective (OR, 0.370).

The H1j subhaplotype is associated with a reduced risk of PSP (OR, 0.201).

MAPT haplotype diversity significantly influences PSP susceptibility.

Abstract

Background: Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disorder characterized by abnormal tau protein aggregation. The MAPT gene encodes for tau protein. The MAPT locus harbors two major haplotypes, H1 and H2, with H1 and its subhaplotypes being associated with an increased risk of PSP. Methods: In this study, we genotyped rs8070723 in a cohort of 73 PSP patients, including 47 PSP Richardson Syndrome (PSP-RS) and 27 PSP variants (vPSP), and 93 age-matched healthy controls (HC) from Southern Italy. Results: Haplotype analysis identified H1 and H2 haplotypes that conferred a risk (OR, 2.620; 95% CI, 1.399–5.140; p = 0.0035) and a protective effect (OR, 0.370; 95% CI, 0.196–0.695; p = 0.0015), respectively. In addition, we genotyped five MAPT variants (rs1467967, rs242557, rs3785883, rs2471738, and rs7521) that, together with rs8070723, defined H1 subhaplotypes. We identified 18 distinct MAPT H1 subhaplotypes, among which H1j displayed a nominally significant reduced risk of PSP (OR, 0.201; 95% CI, 0.044–0.915; p = 0.0265). Conclusions: These findings reinforce the role of MAPT genetic variation in PSP pathogenesis and highlight the potential impact of haplotype diversity on disease susceptibility.

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