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MAPT H1 Haplotype is Associated with Late-Onset Alzheimer’s Disease Risk in APOE ɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium

2015; IOS Press; Volume: 49; Issue: 2 Linguagem: Inglês

10.3233/jad-150555

1875-8908

Pau Pástor, Fermín Moreno, Jordi Clarimón, Agustı́n Ruiz, Onofre Combarros, Miguel Calero, Adolfo López de Munain, María J. Bullido, Marian M. de Pancorbo, Eva Carro, Anna Antonell, Eliécer Coto, Sara Ortega‐Cubero, Isabel Hernández, Lluís Tárraga, Merçé Boada, Alberto Lleó, Oriol Dols‐Icardo, Jaime Kulisevsky, José Luis Vázquez‐Higuera, Jon Infante, Alberto Rábano, Miguel A. Fernández‐Blázquez, Meritxell Valentí‐Soler, Begoña Indakoetxea, Myriam Barandiarán, Ana Gorostidi, Ana Frank, Isabel Sastre, Elena Lorenzo, María A. Pastor, Xabier Elcoroaristizabal, Martina Lennarz, Wolfang Maier, Alfredo Ramı́rez, Manuel Serrano‐Ríos, Suzee E. Lee, Pascual Sánchez‐Juan,

RNA regulation and disease

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer’s disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson’s disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.