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

Sonia Moreno-Grau, Itziar de Rojas, Isabel Hernández, Inés Quintela, Laura Montrreal, Montserrat Alegret, Begoña Hernández-Olasagarre, Laura Madrid, Antonio González-Perez, Olalla Maroñas, Maitée Rosende-Roca, Ana Mauleón, Liliana Vargas, Asunción Lafuente, Carla Abdelnour, Octavio Rodríguez-Gómez, Silvia Gil, Miguel Ángel Santos-Santos, Ana Espinosa, Gemma OrtegaÁngela Sanabria, Alba Pérez-Cordón, Pilar Cañabate, Mariola Moreno, Silvia Preckler, Susana Ruiz, Nuria Aguilera, Juan Antonio Pineda, Juan Macías, Emilio Alarcón-Martín, Oscar Sotolongo-Grau, C. Abdelnour, E. Alarcon, A. Benaque, M. Boada, M. Buendia, A. Carracedo, A. Corbatón, S. Diego, A. Gailhajenet, P. García González, M. Guitart, M. Ibarria, J. Macias, E. Martín, M. T. Martínez, M. Marquié, G. Monté-Rubio, A. Orellana, A. Pancho, E. Pelejà, L. M. Real, A. Ruiz, S. Ruiz, M. E. Sáez, A. Sanabria, M. Serrano-Rios, L. Tárraga, S. Valero, A. D. Adarmes-Gómez, V. Álvarez, Goo Amer-Ferrer, M. Antequera, Carmen Antúnez, M. Baquero, M. Bernal, R. Blesa, D. Buiza-Rueda, M. J. Bullido, J. A. Burguera, M. Calero, F. Carrillo, M. Carrión-Claro, M. J. Casajeros, J. Clarimón, J. M. Cruz-Gamero, M. M. de Pancorbo, T. del Ser, M. Diez-Fairen, J. Fortea, Emilio Franco, A. Frank-García, J. M. García-Alberca, S. Garcia Madrona, G. Garcia-Ribas, P. Gómez-Garre, S. Hevilla, S. Jesús, Labrador Espinosa, C. Lage, A. Legaz, A. Lleó, A. López de Munáin, S. López-García, D. Macias, S. Manzanares, M. Marín, J. Marín-Muñoz, T. Marín

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© 2019 The Authors 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.
Original languageEnglish
Pages (from-to)1333-1347
Number of pages15
JournalAlzheimer's and Dementia
Issue number10
Publication statusPublished - 1 Oct 2019


  • Alzheimer's disease
  • Biological pathway
  • Cerebral amyloid angiopathy
  • GWAS
  • Vascular pathology
  • RARE
  • GENE


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