The MAPT H1 Haplotype Is a Risk Factor for Alzheimer's Disease in APOE epsilon 4 Non-carriers

An ancestral inversion of 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene, defines two haplotype clades in Caucasians (H1 and H2). The H1 haplotype has been linked inconsistently with AD. In a previous study, we showed that an SNP tagging this haplotype...

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Detalles Bibliográficos
Autores: Sanchez-Juan, Pascual, Moreno, Sonia, de Rojas, Itziar, Hernandez, Isabel, Valero, Sergi, Alegret, Montserrat, Montrreal, Laura, Garcia Gonzalez, Pablo, Lage, Carmen, Lopez-Garcia, Sara, Rodriguez-Rodriguez, Eloy, Orellana, Adelina, Tarraga, Lluis, Boada, Merce, Ruiz, Agustin, Abdelnour, C., Aguilera, Nuria, Alarcon-Martin, Emilio, Buendia, Marie Annick, Canabate, Pilar, Diego, S., Espinosa, Ana, Gailhajenet, A., Gil, S., Guitart, M., Hernandez, I, Ibarria, M., Lafuente, A., Martin, E., Mauleon, A., Monte-Rubio, G., Montrreal, L., Moreno-Grau, S., Moreno, M., Orellana, A., Ortega, G., Pancho, A., Peleja, E., Perez-Cordon, A., Preckler, S., Rodriguez-Gomez, Octavio, Rosende-Roca, M., Ruiz, A., Ruiz, S., Sanabria, Angela, Santos-Santos, M. A., Sotolongo-Grau, Oscar, Valero, S., Vargas, Liliana, Quintela, Inés, Real, L. M., Carracedo, Ángel, Maronas, O., Corbaton, A., Martinez, M. T., Serrano-Rios, M., Gonzalez Perez, A., Saez, M. E., Macias, J., Pineda, J. A., Adarmes-Gomez, A. D., Buiza-Rueda, D., Carrillo, Fátima, Carrion-Claro, M., Gomez-Garre, P., Jesus, S., Labrador Espinosa, M. A., Macias, D., Mir, P., Perinan-Tocino, T., Blesa, R., Bullido, Maria Jesus, Calero, Miguel, Clarimon, Jordi, Fortea, J., Frank-Garcia, Ana, Lage, C., Lleo, A., Lopez-Garcia, S., Martin Montes, A., Medina, M., Perez Tur, J., Pinol Ripoll, G., Rabano, Alberto, Rodriguez-Rodriguez, E., Sastre, I, Marquie, M., Cruz-Gamero, J. M., Royo, Jose Luis, Alvarez, I., Diez-Fairen, Monica, Pastor, Pau, Alvarez, Victoria, Martinez, C., Menendez-Gonzalez, M., Amer Ferrer, Guillermo, Antequera, M., Antunez, C., Legaz, A., Manzanares, S., Marin-Munoz, J., Martinez, B., Martinez, V, Vicente, M. P., Vivancos, J., Baquero, M., Burguera, J. A., Bernal, M., Franco, E., Marin, M., Rodrigo, S., del Ser, T., Pastor, A. B., Garcia Madrona, S., Garcia-Ribas, G., Casajeros, M. J., de Pancorbo, M. M., Garcia-Alberca, J. M., Hevilla, S., Marin, T., Lopez de Munain, A., Martinez-Lage Alvarez, P., Mendioroz Iriarte, M., Molinuevo, J. L., Real de Asua, D., Sanchez del Valle Diaz, R., GR ACE Study Grp, DEGESCO Consortium
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Conselleria de Salut i Consum del Govern de les Illes Balears
Repositorio:Docusalut
Idioma:inglés
OAI Identifier:oai:docusalut.com:20.500.13003/12631
Acceso en línea:https://hdl.handle.net/20.500.13003/12631
Access Level:acceso abierto
Palabra clave:Alzheimer's disease
MAPT
APOE
genetic association
Descripción
Sumario:An ancestral inversion of 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene, defines two haplotype clades in Caucasians (H1 and H2). The H1 haplotype has been linked inconsistently with AD. In a previous study, we showed that an SNP tagging this haplotype (rs1800547) was associated with AD risk in a large population from the Dementia Genetics Spanish Consortium (DEGESCO) including 4435 cases and 6147 controls. The association was mainly driven by individuals that were non-carriers of the APOE epsilon 4 allele. Our aim was to replicate our previous findings in an independent sample of 4124 AD cases and 3290 controls from Spain (GR@ACE project) and to analyze the effect of the H1 sub-haplotype structure on the risk of AD. The H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0025). Stratification analysis showed that this association was mainly driven by the APOE epsilon 4 non-carriers (OR = 1.15; p = 0.0022). Pooled analysis of both Spanish datasets (n = 17,996) showed that the highest AD risk related to the MAPT H1/H2 haplotype was in those individuals that were the oldest [third tertile (>77 years)] and did not carry APOE epsilon 4 allele (p = 0.001). We did not find a significant association between H1 sub-haplotypes and AD. H1c was nominally associated but lost statistical significance after adjusting by population sub-structure. Our results are consistent with the hypothesis that genetic variants linked to the MAPT H1/H2 are tracking a genuine risk allele for AD. The fact that this association is stronger in APOE epsilon 4 non-carriers partially explains previous controversial results and might be related to a slower alternative causal pathway less dependent on brain amyloid load.

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