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: Moreno‐Grau Sonia , de Rojas Itziar , Hernández Isabel , Quintela Inés , Montrreal Laura , Alegret Montserrat , Hernández‐Olasagarre Begoña , Madrid Laura , González‐Perez Antonio , Maroñas Olalla , Rosende‐Roca Maitée , Mauleón Ana , Vargas Liliana , Lafuente Asunción , Abdelnour Carla , Rodríguez‐Gómez Octavio , Gil Silvia , Santos‐Santos Miguel Ángel , Espinosa Ana , Ortega Gemma , Sanabria Ángela , Pérez‐Cordón Alba , Cañabate Pilar , Moreno Mariola , Preckler Silvia , Ruiz Susana , Aguilera Nuria , Pineda Juan Antonio , Macías Juan , Alarcón‐Martín Emilio , Sotolongo‐Grau Oscar ,   GR@ACE consortium, Abdelnour C. , Aguilera N. , Alarcon E. , Alegret M. , Benaque A. , Boada M. , Buendia M. , Cañabate P. , Carracedo A. , Corbatón A. , de Rojas I. , Diego S. , Espinosa A. , Gailhajenet A. , García González P. , Gil S. , Guitart M. , González Pérez A. , Hernández I. , Ibarria M. , Lafuente A. , Macias J. , Maroñas O. , Martín E. , Martínez M.T. , Marquié M. , Mauleón A. , Monté‐Rubio G. , Montrreal L. , Moreno‐Grau S. , Moreno M. , Orellana A. , Ortega G. , Pancho A. , Pelejà E. , Pérez‐Cordon A. , Pineda J.A. , Preckler S. , Quintela I. , Real L.M. , Rodríguez‐Gómez O. , Rosende‐Roca M. , Ruiz A. , Ruiz S. , Sáez M.E. , Sanabria A. , Santos‐Santos M.A. , Serrano‐Rios M. , Sotolongo‐Grau O. , Tárraga L. , Valero S. , Vargas L. ,   DEGESCO consortium, Adarmes‐Gómez A.D. , Alarcón‐Martín E. , Álvarez I. , Álvarez V. , Amer‐Ferrer Goo , Antequera M. , Antúnez C. , Baquero M. , Bernal M. , Blesa R. , Boada M. , 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. , de Rojas I. , 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. , Hernández I. , Hevilla S. , Jesús S. , Espinosa Labrador , Lage C. , Legaz A. , Lleó A. , López de Munáin A. , López‐García S. , Macias D. , Manzanares S. , Marín M. , Marín‐Muñoz J. , Marín T. , Marquié M. , 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. , Monté‐Rubio G. , Montrreal L. , Moreno‐Grau S. , Orellana A. , Pastor A.B. , Pastor P. , Pérez Tur J. , Periñán‐Tocino T. , Piñol Ripoll G. , Rábano A. , Real de Asúa D. , Rodrigo S. , Rodríguez‐Rodríguez E. , Royo J.L. , A Ruiz , Sanchez del Valle Díaz R. , Sánchez‐Juan P. , Sastre I. , Sotolongo‐Grau O. , Tárraga L. , Valero S. , Vicente M.P. , Vivancos L. ,   Alzheimer's Disease Neuroimaging Initiative, Marquié Marta , Monté‐Rubio Gemma , Valero Sergi , Benaque Alba , Clarimón Jordi , Bullido Maria Jesus , García‐Ribas Guillermo , Pástor Pau , Sánchez‐Juan Pascual , Álvarez Victoria , Piñol‐Ripoll Gerard , García‐Alberca Jose Maria , Royo José Luis , Franco Emilio , Mir Pablo , Calero Miguel , Medina Miguel , Rábano Alberto , Ávila Jesús , Antúnez Carmen , Real Luis Miguel , Orellana Adelina , Carracedo Ángel , Sáez María Eugenia , Tárraga Lluís , Boada Mercè , Ruiz Agustín 
Published: August 2019

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.