MAPT Subhaplotypes in Different Progressive Supranuclear Palsy Phenotypes

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