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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

2019; Wiley; Volume: 15; Issue: 10 Linguagem: Inglês

10.1016/j.jalz.2019.06.4950

1552-5279

Sonia Moreno‐Grau, Itziar de Rojas, Isabel Hernández, Inés Quintela, Laura Montrreal, Montserrat Alegret, Begoña Hernández‐Olasagarre, Laura Madrid, Antonio González‐Pérez, Olalla Maroñas, Maiteé Rosende‐Roca, Ana Mauleón, Liliana Vargas, Asunción Lafuente, Carla Abdelnour, Octavio Rodríguez‐Gómez, Silvia Gil, Miguel A. Santos‐Santos, Ana Espinosa, Gemma Ortega, Ángela Sanabria, Alba Pérez‐Cordón, Pilar Cañabate, Mariola Moreno, Sílvia Preckler, Susana Ruiz, Núria Aguilera, Juan A. Pineda, Juan Macı́as, Emilio Alarcón‐Martín, Óscar Sotolongo‐Grau, Carla Abdelnour, N. Aguilera, Emilio Alarcón‐Martín, Montserrat Alegret, Alba Benaque, Merçé Boada, Mar Buendía, Pilar Cañabate, Ángel Carracedo, Arturo Corbatón Anchuelo, Itziar de Rojas, S. Diego, Ana Espinosa, A. Gailhajenet, Pablo García‐González, Silvia Gil, M. Guitart, Antonio González‐Pérez, Iván Hernández Ramírez, Marta Ibarria, A. Lafuente, Juan Macı́as, Olalla Maroñas, Eden R. Martin, María Teresa González Martínez, Marta Marquié, Ana Mauleón, Gemma C. Monté, Laura Montrreal, Sonia Moreno‐Grau, M. Moreno, Adelina Orellana, Gemma Ortega, A. Pancho, E. Pelejà, Alba Pérez‐Cordón, Juan A. Pineda, Sílvia Preckler, Inés Quintela, Luís Miguel Real, Octavio Rodríguez‐Gómez, Maiteé Rosende‐Roca, Agustı́n Ruiz, Susana Ruiz, María Eugenia Sáez, Ángela Sanabria, Miguel A. Santos‐Santos, Manuel Serrano‐Ríos, Óscar Sotolongo‐Grau, Lluís Tárraga, Sergi Valero, Liliana Vargas, Astrid Adarmes‐Gómez, Emilio Alarcón‐Martín, Ignacio Álvarez, Victoria Álvarez, G. Amer-Ferrer, M. Antequera, Carmen Antúnez, Miquel Baquero, M. Bernal, Rafael Blesa, Merçé Boada, Dolores Buiza‐Rueda, María J. Bullido, J A Burguera, Miguel Calero, F. Carrillo, Mario Carrión‐Claro, M. J. Casajeros, Jordi Clarimón, J. M. Cruz-Gamero, Marian M. de Pancorbo, Itziar de Rojas, Teodoro del Ser, Mónica Díez-Fairén, Juan Fortea, Emilio Franco, Ana Frank, José María García‐Alberca, S. García Madrona, Guillermo García‐Ribas, Pilar Gómez‐Garre, Israel Hernández, S. Hevilla, Silvia Jesús, Labrador Espinosa, Carmen Lage, Agustina Legaz, Alberto Lleó, Adolfo López de Munain, Sergio López‐García, Daniel Macías, Salvadora Manzanares, M. Marín, Juan Marín-Muñoz, Teresa J. Marin, Marta Marquié, Ángel Martín Montes, B. Martínez, Carmen Martı́nez, Verónica S. Martínez, Pablo Martínez-Lage Álvarez, Miguel Medina, Maite Mendióroz, Manuel Menéndez‐González, Pablo Mir, J.L. Molinuevo, Gemma C. Monté, Laura Montrreal, Sonia Moreno‐Grau, Adelina Orellana, Ana Belén Pastor, Pau Pástor, Jordi Pérez‐Tur, María Teresa Periñán, G. Piñol Ripoll, Alberto Rábano, Diego Real de Asúa, S. Rodrigo, Eloy Rodríguez‐Rodríguez, José Luís Royo, Agustı́n Ruiz, R. Sanchez del Valle Díaz, Pascual Sánchez‐Juan, Isabel Sastre, Óscar Sotolongo‐Grau, Luis Tárraga, Sergi Valero, M.P. Vicente, L. Vivancos, Marta Marquié, Gemma C. Monté, Sergi Valero, Alba Benaque, Jordi Clarimón, María J. Bullido, Guillermo García‐Ribas, Pau Pástor, Pascual Sánchez‐Juan, Victoria Álvarez, Gerard Piñol‐Ripoll, José María García‐Alberca, José Luís Royo, Emilio Franco, Pablo Mir, Miguel Calero, Miguel Medina, Alberto Rábano, Jesús Ávila, Carmen Antúnez, Luís Miguel Real, Adelina Orellana, Ángel Carracedo, María Eugenia Sáez, Lluís Tárraga, Merçé Boada, Agustı́n Ruiz,

Bioinformatics and Genomic Networks

Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways.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.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.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.