Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project
Moreno-Grau, S.; de Rojas, I.; Hernández, I.; Quintela, I.; Montrreal, L.; Alegret, M.; Hernández-Olasagarre, B.; Madrid, L.; González-Perez, A.; Maroñas, O.; Rosende-Roca, M.; Mauleón, A.; Vargas, L.; Lafuente, A.; Abdelnour, C.; Rodríguez-Gómez, O.; Gil, S.; Santos-Santos, M. Á; Espinosa, A.; Ortega, G.; Sanabria, Á; Pérez-Cordón, A.; Cañabate, P.; Moreno, M.; Preckler, S.; Ruiz, S.; Aguilera, N.; Pineda, J. A.; Macías, J.; Alarcón-Martín, E.; Sotolongo-Grau, O.; Abdelnour, C.; Alarcon, E.; Benaque, A.; Boada, M.; Buendia, M.; Carracedo Álvarez, Ángel; Corbatón, A.; Diego, S.; Gailhajenet, A.; García González, P.; Guitart, M.; Ibarria, M.; Macias, J.; Martín, E.; Martínez, M. T.; Marquié, M.; Monté-Rubio, G.; Orellana, A.; Pancho, A.; Pelejà, E.; Real, L. M.; Ruiz, A.; Ruiz, S.; Sáez, M. E.; Sanabria, A.; Serrano-Rios, M.; Tárraga, L.; Valero, S.; Adarmes-Gómez, A. D.; Álvarez, I.; Álvarez, V.; Amer-Ferrer, G.; Antequera, M.; Antúnez, C.; Baquero, M.; Bernal, M.; Blesa, R.; Buiza-Rueda, D.; Bullido, M. J.; Burguera, J. A.; Calero, M.; Carrillo, F.; Carrión-Claro, M.; Casajeros, M. J.; Clarimón, J.; Cruz-Gamero, J. M.; de Pancorbo, M. M.; del Ser, T.; Diez-Fairen, M.; Fortea, J.; Franco, E.; Frank-García, A.; García-Alberca, J. M.; Garcia Madrona, S.; Garcia-Ribas, G.; Gómez-Garre, P.; Hevilla, S.; Jesús, S.; Espinosa, L.; Lage, C.; Legaz, A.; Lleó, A.; López de Munáin, A.; López-García, S.; Macias, D.; Manzanares, S.; Marín, M.; Marín-Muñoz, J.; Marín, T.; Martín Montes, A.; Martínez, B.; Martínez, C.; Martínez, V.; Martínez-Lage Álvarez, P.; Medina, M.; Mendioroz Iriarte, M.; Menéndez-González, M.; Mir, P.; Molinuevo, J. L.; Pastor, A. B.; Pástor, P.; Pérez Tur, J.; Periñán-Tocino, T.; Piñol Ripoll, G.; Rábano, A.; Real de Asúa, D.; Rodrigo, S.; Rodríguez-Rodríguez, E.; Royo, J. L.; Ruiz, A.; Sanchez del Valle Díaz, R.; Sánchez-Juan, P.; Sastre, I.; Vicente, M. P.; Vivancos, L.; García-Ribas, G.; Piñol-Ripoll, G.; Medina, M.; Ávila, J.
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Identificadores
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Fecha de publicación
2019Título de revista
Alzheimers Dement
Tipo de contenido
Artigo
DeCS
endofenotipos | anciano | angiopatía amiloide cerebral | enfermedad de Alzheimer | mediana edad | humanos | estudio de asociación genómica completa | sitios genéticos | predisposición genética a la enfermedad | demenciaMeSH
Cerebral Amyloid Angiopathy | Alzheimer Disease | Genetic Loci | Dementia | Middle Aged | Humans | Endophenotypes | Genome-Wide Association Study | Genetic Predisposition to Disease | AgedResumen
INTRODUCTION: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. METHODS: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. RESULTS: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. DISCUSSION: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.
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