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Alzheimers Dement. 2019 Oct;15(10):1333-1347. doi: 10.1016/j.jalz.2019.06.4950. Epub 2019 Aug 28.

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.

Collaborators (131)

Abdelnour C26, Aguilera N27, Alarcon E28, Alegret M26, Benaque A27, Boada M26, Buendia M27, Cañabate P26, Carracedo A24, Corbatón A29, de Rojas I27, Diego S27, Espinosa A26, Gailhajenet A27, García González P27, Gil S27, Guitart M27, González Pérez A4, Hernández I26, Ibarria M27, Lafuente A27, Macias J5, Maroñas O3, Martín E27, Martínez MT29, Marquié M27, Mauleón A27, Monté-Rubio G27, Montrreal L27, Moreno-Grau S26, Moreno M27, Orellana A27, Ortega G26, Pancho A27, Pelejà E27, Pérez-Cordon A27, Pineda JA5, Preckler S27, Quintela I30, Real LM31, Rodríguez-Gómez O26, Rosende-Roca M27, Ruiz A26, Ruiz S26, Sáez ME4, Sanabria A26, Santos-Santos MA27, Serrano-Rios M29, Sotolongo-Grau O27, Tárraga L26, Valero S26, Vargas L27, Adarmes-Gómez AD32, Alarcón-Martín E6, Álvarez I33, Álvarez V12, Amer-Ferrer G, Antequera M34, Antúnez C34, Baquero M35, Bernal M36, Blesa R37, Boada M38, Buiza-Rueda D32, Bullido MJ39, Burguera JA35, Calero M40, Carrillo F32, Carrión-Claro M32, Casajeros MJ41, Clarimón J37, Cruz-Gamero JM15, de Pancorbo MM42, de Rojas I2, Del Ser T43, Diez-Fairen M33, Fortea J37, Franco E36, Frank-García A44, García-Alberca JM14, Garcia Madrona S45, Garcia-Ribas G45, Gómez-Garre P32, Hernández I38, Hevilla S14, Jesús S32, Espinosa L32, Lage C46, Legaz A34, Lleó A37, López de Munáin A47, López-García S46, Macias D32, Manzanares S48, Marín M36, Marín-Muñoz J34, Marín T14, Marquié M2, Martín Montes A49, Martínez B34, Martínez C50, Martínez V51, Martínez-Lage Álvarez P52, Medina M53, Mendioroz Iriarte M54, Menéndez-González M55, Mir P32, Molinuevo JL56, Monté-Rubio G2, Montrreal L2, Moreno-Grau S38, Orellana A2, Pastor AB57, Pastor P33, Pérez Tur J58, Periñán-Tocino T32, Piñol Ripoll G59, Rábano A60, Real de Asúa D61, Rodrigo S36, Rodríguez-Rodríguez E46, Royo JL15, A R38, Sanchez Del Valle Díaz R62, Sánchez-Juan P46, Sastre I63, Sotolongo-Grau O2, Tárraga L38, Valero S38, Vicente MP34, Vivancos L34.

Author information

1
Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
2
Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.
3
Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3-ISCIII). Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
4
CAEBI, Centro Andaluz de Estudios Bioinformáticos, Sevilla, Spain.
5
Unidad Clínica de Enfermedades Infecciosas y Microbiología. Hospital Universitario de Valme, Sevilla, Spain.
6
Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain.
7
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
8
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; Centro de Biologia Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autonoma de Madrid, Madrid, Spain; Instituto de Investigacion Sanitaria "Hospital la Paz" (IdIPaz), Madrid, Spain.
9
Hospital Universitario Ramón y Cajal, Madrid, Spain.
10
Fundació per la Recerca Biomèdica i Social Mútua Terrassa, and Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, University of Barcelona School of Medicine, Terrassa, Spain.
11
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; Neurology Service 'Marqués de Valdecilla' University Hospital (University of Cantabria and IDIVAL), Santander, Spain.
12
Laboratorio de Genética Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
13
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Institut de Recerca Biomédica de Lleida (IRBLLeida), Lleida, Spain.
14
Alzheimer Research Center & Memory Clinic, Andalusian Institute for Neuroscience, Málaga, Spain.
15
Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain.
16
Unidad de Demencias, Servicio de Neurología y Neurofisiología. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
17
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
18
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Madrid, Spain; Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
19
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Madrid, Spain.
20
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Madrid, Spain; BT-CIEN, Madrid, Spain.
21
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid (UAM), Madrid, Spain.
22
Unidad de Demencias, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
23
Unidad Clínica de Enfermedades Infecciosas y Microbiología. Hospital Universitario de Valme, Sevilla, Spain; Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain.
24
Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3-ISCIII). Universidade de Santiago de Compostela, Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica- CIBERER-IDIS, Santiago de Compostela, Spain.
25
Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain. Electronic address: aruiz@fundacioace.org.
26
Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades. Universitat Internacional de Catalunya, Barcelona, Spain; CIBERNED, Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Spain.
27
Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades. Universitat Internacional de Catalunya, Barcelona, Spain.
28
Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades. Universitat Internacional de Catalunya, Barcelona, Spain; Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga Málaga, Spain.
29
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Spain, Hospital Clínico San Carlos, Madrid, Spain.
30
Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga Málaga, Spain.
31
Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga Málaga, Spain; Unidad Clínica de Enfermedades Infecciosas y Microbiología. Hospital Universitario de Valme, Sevilla, Spain.
32
Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain.
33
Fundació per la Recerca Biomèdica i Social Mútua Terrassa, and Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain.
34
Unidad de Demencias, Hospital Clínico Universitario Virgen de la Arrixaca, Spain.
35
Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
36
Unidad de Demencias, Servicio de Neurología y Neurofisiología, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
37
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain; Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
38
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain; Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.
39
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain; Centro de Biologia Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autonoma de Madrid, Madrid, Spain; Instituto de Investigacion Sanitaria 'Hospital la Paz' (IdIPaz), Madrid, Spain.
40
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain; CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Madrid, Spain; Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
41
Hospital Universitario Ramón y Cajal; Madrid, Spain.
42
BIOMICs, País Vasco; Centro de Investigación Lascaray, Universidad del País Vasco UPV/EHU.
43
Instituto de Investigacion Sanitaria 'Hospital la Paz' (IdIPaz), Madrid, Spain.
44
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain; Instituto de Investigacion Sanitaria 'Hospital la Paz' (IdIPaz), Madrid, Spain; Neurology Service, Hospital Universitario La Paz (UAM), Madrid, Spain.
45
Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
46
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain; Neurology Service, Marqués de Valdecilla University Hospital (University of Cantabria and IDIVAL), Santander, Spain.
47
Hospital Donostia de San Sebastían.
48
Unidad de Demencias, Hospital Clínico Universitario Virgen de la Arrixaca, Spain; Fundación para la Formación e Investigación Sanitarias de la Región de Murcia, Murcia, Spain.
49
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain; Centro de Biologia Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autonoma de Madrid, Madrid, Spain; Neurology Service, Hospital Universitario La Paz (UAM), Madrid, Spain.
50
Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Servicio de Neurología -Hospital de Cabueñes-Gijón.
51
Department of Neurology, Hospital Universitario Son Espases, Palma, Spain.
52
Centro de Investigación y Terapias Avanzadas, Fundación CITA-alzheimer, San Sebastián, Spain.
53
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain; Instituto de Investigacion Sanitaria 'Hospital la Paz' (IdIPaz), Madrid, Spain.
54
Navarrabiomed, Pamplona, Spain.
55
Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Servicio de Neurología -Hospital Universitario Central de Asturias, Oviedo, Spain.
56
Barcelona βeta Brain Research Center - Fundació Pasqual Maragall, Barcelona, Spain.
57
CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Madrid, Spain.
58
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain; Unitat de Genètica Molecular, Institut de Biomedicina de València-CSIC, Valencia, Spain; Unidad Mixta de Neurologia Genètica, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
59
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain; Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Institut de Recerca Biomédica de Lleida (IRBLLeida), Lleida, Spain.
60
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain; CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Madrid, Spain; BT-CIEN, Madrid, Spain.
61
Hospital Universitario La Princesa, Madrid, Spain.
62
Hospital Clínic Barcelona, Barcelona, Spain.
63
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Spain; Centro de Biologia Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autonoma de Madrid, Madrid, Spain.

Abstract

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.

KEYWORDS:

Alzheimer's disease; Biological pathway; Cerebral amyloid angiopathy; GWAS; Vascular pathology

PMID:
31473137
DOI:
10.1016/j.jalz.2019.06.4950
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