Identifier to cite or link to this item: http://hdl.handle.net/20.500.13003/12631
The MAPT H1 Haplotype Is a Risk Factor for Alzheimer's Disease in APOE epsilon 4 Non-carriers
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ISSN: 1663-4365
WOS ID: 000503234400001
Scopus EID: 2-s2.0-85077263835
PMID: 31866851
Embase PUI: L630230975
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Sanchez-Juan, Pascual; Moreno, Sonia; de Rojaso, Itziar; Hernandez, Isabel; Valero, Sergi; Alegret, Montse; Montrreal, Laura; Garcia Gonzalez, Pablo; Lage, Carmen; Lopez-Garcia, Sara; Rodriiguez-Rodriguez, Eloy; Orellana, Adelina; Tarraga, Lluis; Boada, Merce; Ruiz, Agustin; Abdelnour, C.; Aguilera, N.; Alarcon, E.; Alegret, M.; Boada, M.; Buendia, M.; Canabate, P.; de Rojas, I; Diego, S.; Espinosa, A.; Gailhajenet, A.; Garcia Gonzalez, P.; 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, O.; Rosende-Roca, M.; Ruiz, A.; Ruiz, S.; Sanabria, A.; Santos-Santos, M. A.; Sotolongo-Grau, O.; Tarraga, L.; Valero, S.; Vargas, L.; Quintela, I; Real, L. M.; Carracedo, A.; 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, F.; Carrion-Claro, M.; Gomez-Garre, P.; Jesus, S.; Labrador Espinosa, M. A.; Macias, D.; Mir, P.; Perinan-Tocino, T.; Blesa, R.; Bullido, M. J.; Calero, M.; Clarimon, J.; Fortea, J.; Frank-Garcia, A.; Lage, C.; Lleo, A.; Lopez-Garcia, S.; Martin Montes, A.; Medina, M.; Perez Tur, J.; Pinol Ripoll, G.; Rabano, A.; Rodriguez-Rodriguez, E.; Sanchez-Juan, P.; Sastre, I; Alarcon-Martin, E.; Marquie, M.; Cruz-Gamero, J. M.; Royo, J. L.; 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, M. P.; Vivancos, L.; 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.; del Valle Diaz, R. Sanchez; GR ACE Study Grp; DEGESCO ConsortiumPublication date
2019-12-04Document type
research articleCitation
Sanchez-Juan P, Moreno S, De Rojaso I, Hernandez I, Valero S, Alegret M, et al. The MAPT H1 Haplotype Is a Risk Factor for Alzheimer's Disease in APOE epsilon 4 Non-carriers. Front Aging Neurosci. 2019 Dec 04;11:327.Abstract
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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https://dx.doi.org/10.3389/fnagi.2019.00327Keywords
Alzheimer's diseaseMAPT
APOE
genetic association
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