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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Authors: Sanchez-Juan, P, Moreno, S, de Rojaso, I, Hernandez, I, Valero, S, Alegret, M, Montrreal, L, Gonzalez, PG, Lage, C, Lopez-Garcia, S, Rodriiguez-Rodriguez, E, Orellana, A, Tarraga, L, Boada, M, Ruiz, A, Abdelnour, C, Aguilera, N, Alarcon, E, Buendia, M, Canabate, P, de Rojas, I, Diego, S, Espinosa, A, Gailhajenet, A, Gil, S, Guitart, M, Ibarria, M, Lafuente, A, Martin, E, Mauleon, A, Monte-Rubio, G, Moreno-Grau, S, Moreno, M, Ortega, G, Pancho, A, Peleja, E, Perez-Cordon, A, Preckler, S, Rodriguez-Gomez, O, Rosende-Roca, M, Ruiz, S, Sanabria, A, Santos-Santos, MA, Sotolongo-Grau, O, Vargas, L, Quintela, I, Real, LM, Carracedo, A, Maronas, O, Corbaton, A, Martinez, MT, Serrano-Rios, M, Perez, AG, Saez, ME, Macias, J, Pineda, JA, Adarmes-Gomez, AD, Buiza-Rueda, D, Carrillo, F, Carrion-Claro, M, Gomez-Garre, P, Jesus, S, Espinosa, MAL, Macias, D, Mir, P, Perinan-Tocino, T, Blesa, R, Bullido, MJ, Calero, M, Clarimon, J, Fortea, J, Frank-Garcia, A, Lleo, A, Montes, AM, Medina, M, Tur, JP, Ripoll, GP, Rabano, A, Rodriguez-Rodriguez, E, Sastre, I, Alarcon-Martin, E, Marquie, M, Cruz-Gamero, JM, Royo, JL, Alvarez, I, Diez-Fairen, M, Pastor, P, Alvarez, V, Martinez, C, Menendez-Gonzalez, M, Amer-Ferrer, G, Antequera, M, Antunez, C, Legaz, A, Manzanares, S, Marin-Munoz, J, Martinez, B, Martinez, V, Vicente, MP, Vivancos, L, Baquero, M, Burguera, JA, Bernal, M, Franco, E, Marin, M, Rodrigo, S, del Ser, T, Pastor, AB, Madrona, SG, Garcia-Ribas, G, Casajeros, MJ, de Pancorbo, MM, Garcia-Alberca, JM, Hevilla, S, Marin, T, de Munain, AL, Alvarez, PML, Iriarte, MM, Molinuevo, JL, de Asua, DR, Diaz, RSD
Format: article
Status:Published version
Publication Date:2019
Country:España
Institution:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repository:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p13716
Online Access:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=13716
Access Level:Open access
Keyword:Alzheimer's disease
MAPT
APOE
genetic association
Description
Summary: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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