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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

Authors
Sonia Moreno–Grau,Itziar Rojas
Isabel Hernández,Inés Quintela,Laura Montrreal,Montserrat Alegret,Begoña Hernández-Olasagarre,Laura Madrid,Antonio González‐Pérez,Olalla Maroñas,Maitée Rosende-Roca,Ana Mauleón,Liliana Vargas,Asunción Lafuente,Carla Abdelnour,Octavio Rodríguez-Gómez,Silvia Gil,Miguel Santos‐Santos,Ana Espinosa,Gemma Ortega,Ángela Sanabria,Alba Pérez‐Cordón,Pilar Cañabate,Mariola Moreno,Silvia Preckler,Susana Ruiz,Núria Aguilera,Juan Pineda,Juan Macı́as,Emilio Alarcón‐Martín,Oscar Sotolongo‐Grau,Emilio Alarcon,Alba Benaque,Merçé Boada,Mar Buendía,Ángel Carracedo,Arturo Corbatón,Susana Diego,A. Gailhajenet,Pablo García‐González,Marina Guitart,Marta Ibarria,Eden Martin,María Martínez,Marta Marquié,Gemma Monte‐Rubio,Adelina Orellana,Ana Pancho,E. Pelejá,Luís Real,Agustín Ruiz,María Sáez,Manuel Serrano-Rı́os,Lluís Tárraga,Sergi Valero,A. Gómez,Victoria Álvarez,G. Amer-Ferrer,M. Antequera,Carmen Antúnez,Miquel Baquero,María Bernal,Rafael Blesa,Dolores Buiza‐Rueda,María Bullido,J.A. Burguera,Miguel Calero,Fátima Carrillo,Mario Carrión‐Claro,M. Casajeros,Jordi Clarimón,Begoña Hernández‐Olasagarre,Maitée Rosende‐Roca,Octavio Rodríguez‐Gómez,Phyoe Sithu,Óscar Sotolongo‐Grau,M. Guitart,Gemma Monté‐Rubio,E. Pelejà,J Burguera,José Cruz‐Gamero,Marian Pancorbo,Teodoro Ser,Mónica Díez-Fairén,Juan Fortea,Emilio Franco,Ana Frank‐García,José García‐Alberca,S. Madrona,Guillermo García‐Ribas,Pilar Gómez‐Garre,Israel Hernández,S. Hevilla,Silvia Jesús,Léon Espinosa,Carmen Lage,Agustina Legaz,Alberto Lleó,Adolfo Munaín,Sergio López‐García,Daniel Macías,Sandra Manzanares,M. Marín,Juan Marín-Muñoz,Teresa Marin,Ángel Montes,B. Martínez,Carmen Martı́nez,Verónica Martínez,Pablo Álvarez,Miguel Medina,Maite Mendioroz,Manuel Menéndez‐González,Pablo Mir,José-Luis Molinuevo,Ana Pastor,Pau Pástor,Jordi Pérez‐Tur,María Periñán,G. Ripoll,Alberto Rábano,Diego Asúa,S. Rodrigo,Elena Rodríguez‐Rodríguez,José Royo,Asier Ruiz,R. Díaz,Pascual Sánchez‐Juan,Isabel Sastre,Luis Tárraga,M.P. Vicente,Leandro Vivancos,Gerard Piñol‐Ripoll
+131 authors
,Jesús Ávila
Published
Aug 28, 2019
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Abstract

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.

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