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
Sonia Moreno-Grau
1
, Itziar de Rojas
2
, Isabel Hernández
1
, Inés Quintela
3
, Laura Montrreal
2
, Montserrat Alegret
1
, Begoña Hernández-Olasagarre
2
, Laura Madrid
4
, Antonio González-Perez
4
, Olalla Maroñas
3
, Maitée Rosende-Roca
2
, Ana Mauleón
2
, Liliana Vargas
2
, Asunción Lafuente
2
, Carla Abdelnour
1
, Octavio Rodríguez-Gómez
1
, Silvia Gil
2
, Miguel Ángel Santos-Santos
2
, Ana Espinosa
1
, Gemma Ortega
1
, Ángela Sanabria
1
, Alba Pérez-Cordón
2
, Pilar Cañabate
1
, Mariola Moreno
2
, Silvia Preckler
2
, Susana Ruiz
1
, Nuria Aguilera
2
, Juan Antonio Pineda
5
, Juan Macías
5
, Emilio Alarcón-Martín
6
, Oscar Sotolongo-Grau
2
; GR@ACE consortium; DEGESCO consortium; Alzheimer's Disease Neuroimaging Initiative; Marta Marquié
2
, Gemma Monté-Rubio
2
, Sergi Valero
1
, Alba Benaque
2
, Jordi Clarimón
7
, Maria Jesus Bullido
8
, Guillermo García-Ribas
9
, Pau Pástor
10
, Pascual Sánchez-Juan
11
, Victoria Álvarez
12
, Gerard Piñol-Ripoll
13
, Jose Maria García-Alberca
14
, José Luis Royo
15
, Emilio Franco
16
, Pablo Mir
17
, Miguel Calero
18
, Miguel Medina
19
, Alberto Rábano
20
, Jesús Ávila
21
, Carmen Antúnez
22
, Luis Miguel Real
23
, Adelina Orellana
2
, Ángel Carracedo
24
, María Eugenia Sáez
4
, Lluís Tárraga
1
, Mercè Boada
1
, Agustín Ruiz
25
Collaborators,
Affiliations
Collaborators
-
C Abdelnour 26 , N Aguilera 27 , E Alarcon 28 , M Alegret 26 , A Benaque 27 , M Boada 26 , M Buendia 27 , P Cañabate 26 , A Carracedo 24 , A Corbatón 29 , I de Rojas 27 , S Diego 27 , A Espinosa 26 , A Gailhajenet 27 , P García González 27 , S Gil 27 , M Guitart 27 , A González Pérez 4 , I Hernández 26 , M Ibarria 27 , A Lafuente 27 , J Macias 5 , O Maroñas 3 , E Martín 27 , M T Martínez 29 , M Marquié 27 , A Mauleón 27 , G Monté-Rubio 27 , L Montrreal 27 , S Moreno-Grau 26 , M Moreno 27 , A Orellana 27 , G Ortega 26 , A Pancho 27 , E Pelejà 27 , A Pérez-Cordon 27 , J A Pineda 5 , S Preckler 27 , I Quintela 30 , L M Real 31 , O Rodríguez-Gómez 26 , M Rosende-Roca 27 , A Ruiz 26 , S Ruiz 26 , M E Sáez 4 , A Sanabria 26 , M A Santos-Santos 27 , M Serrano-Rios 29 , O Sotolongo-Grau 27 , L Tárraga 26 , S Valero 26 , L Vargas 27 , A D Adarmes-Gómez 32 , E Alarcón-Martín 6 , I Álvarez 33 , V Álvarez 12 , Goo Amer-Ferrer, M Antequera 34 , C Antúnez 34 , M Baquero 35 , M Bernal 36 , R Blesa 37 , M Boada 38 , D Buiza-Rueda 32 , M J Bullido 39 , J A Burguera 35 , M Calero 40 , F Carrillo 32 , M Carrión-Claro 32 , M J Casajeros 41 , J Clarimón 37 , J M Cruz-Gamero 15 , M M de Pancorbo 42 , I de Rojas 2 , T Del Ser 43 , M Diez-Fairen 33 , J Fortea 37 , E Franco 36 , A Frank-García 44 , J M García-Alberca 14 , S Garcia Madrona 45 , G Garcia-Ribas 45 , P Gómez-Garre 32 , I Hernández 38 , S Hevilla 14 , S Jesús 32 , Labrador Espinosa 32 , C Lage 46 , A Legaz 34 , A Lleó 37 , A López de Munáin 47 , S López-García 46 , D Macias 32 , S Manzanares 48 , M Marín 36 , J Marín-Muñoz 34 , T Marín 14 , M Marquié 2 , A Martín Montes 49 , B Martínez 34 , C Martínez 50 , V Martínez 51 , P Martínez-Lage Álvarez 52 , M Medina 53 , M Mendioroz Iriarte 54 , M Menéndez-González 55 , P Mir 32 , J L Molinuevo 56 , G Monté-Rubio 2 , L Montrreal 2 , S Moreno-Grau 38 , A Orellana 2 , A B Pastor 57 , P Pastor 33 , J Pérez Tur 58 , T Periñán-Tocino 32 , G Piñol Ripoll 59 , A Rábano 60 , D Real de Asúa 61 , S Rodrigo 36 , E Rodríguez-Rodríguez 46 , J L Royo 15 , Ruiz A 38 , R Sanchez Del Valle Díaz 62 , P Sánchez-Juan 46 , I Sastre 63 , O Sotolongo-Grau 2 , L Tárraga 38 , S Valero 38 , M P Vicente 34 , L Vivancos 34
Affiliations
- 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.
- PMID: 31473137
- DOI: 10.1016/j.jalz.2019.06.4950
Item in Clipboard
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 et al.
Alzheimers Dement.
2019 Oct.
Free article
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Format
doi: 10.1016/j.jalz.2019.06.4950.
Epub 2019 Aug 28.
Authors
Sonia Moreno-Grau
1
, Itziar de Rojas
2
, Isabel Hernández
1
, Inés Quintela
3
, Laura Montrreal
2
, Montserrat Alegret
1
, Begoña Hernández-Olasagarre
2
, Laura Madrid
4
, Antonio González-Perez
4
, Olalla Maroñas
3
, Maitée Rosende-Roca
2
, Ana Mauleón
2
, Liliana Vargas
2
, Asunción Lafuente
2
, Carla Abdelnour
1
, Octavio Rodríguez-Gómez
1
, Silvia Gil
2
, Miguel Ángel Santos-Santos
2
, Ana Espinosa
1
, Gemma Ortega
1
, Ángela Sanabria
1
, Alba Pérez-Cordón
2
, Pilar Cañabate
1
, Mariola Moreno
2
, Silvia Preckler
2
, Susana Ruiz
1
, Nuria Aguilera
2
, Juan Antonio Pineda
5
, Juan Macías
5
, Emilio Alarcón-Martín
6
, Oscar Sotolongo-Grau
2
; GR@ACE consortium; DEGESCO consortium; Alzheimer's Disease Neuroimaging Initiative; Marta Marquié
2
, Gemma Monté-Rubio
2
, Sergi Valero
1
, Alba Benaque
2
, Jordi Clarimón
7
, Maria Jesus Bullido
8
, Guillermo García-Ribas
9
, Pau Pástor
10
, Pascual Sánchez-Juan
11
, Victoria Álvarez
12
, Gerard Piñol-Ripoll
13
, Jose Maria García-Alberca
14
, José Luis Royo
15
, Emilio Franco
16
, Pablo Mir
17
, Miguel Calero
18
, Miguel Medina
19
, Alberto Rábano
20
, Jesús Ávila
21
, Carmen Antúnez
22
, Luis Miguel Real
23
, Adelina Orellana
2
, Ángel Carracedo
24
, María Eugenia Sáez
4
, Lluís Tárraga
1
, Mercè Boada
1
, Agustín Ruiz
25
Collaborators
-
C Abdelnour 26 , N Aguilera 27 , E Alarcon 28 , M Alegret 26 , A Benaque 27 , M Boada 26 , M Buendia 27 , P Cañabate 26 , A Carracedo 24 , A Corbatón 29 , I de Rojas 27 , S Diego 27 , A Espinosa 26 , A Gailhajenet 27 , P García González 27 , S Gil 27 , M Guitart 27 , A González Pérez 4 , I Hernández 26 , M Ibarria 27 , A Lafuente 27 , J Macias 5 , O Maroñas 3 , E Martín 27 , M T Martínez 29 , M Marquié 27 , A Mauleón 27 , G Monté-Rubio 27 , L Montrreal 27 , S Moreno-Grau 26 , M Moreno 27 , A Orellana 27 , G Ortega 26 , A Pancho 27 , E Pelejà 27 , A Pérez-Cordon 27 , J A Pineda 5 , S Preckler 27 , I Quintela 30 , L M Real 31 , O Rodríguez-Gómez 26 , M Rosende-Roca 27 , A Ruiz 26 , S Ruiz 26 , M E Sáez 4 , A Sanabria 26 , M A Santos-Santos 27 , M Serrano-Rios 29 , O Sotolongo-Grau 27 , L Tárraga 26 , S Valero 26 , L Vargas 27 , A D Adarmes-Gómez 32 , E Alarcón-Martín 6 , I Álvarez 33 , V Álvarez 12 , Goo Amer-Ferrer, M Antequera 34 , C Antúnez 34 , M Baquero 35 , M Bernal 36 , R Blesa 37 , M Boada 38 , D Buiza-Rueda 32 , M J Bullido 39 , J A Burguera 35 , M Calero 40 , F Carrillo 32 , M Carrión-Claro 32 , M J Casajeros 41 , J Clarimón 37 , J M Cruz-Gamero 15 , M M de Pancorbo 42 , I de Rojas 2 , T Del Ser 43 , M Diez-Fairen 33 , J Fortea 37 , E Franco 36 , A Frank-García 44 , J M García-Alberca 14 , S Garcia Madrona 45 , G Garcia-Ribas 45 , P Gómez-Garre 32 , I Hernández 38 , S Hevilla 14 , S Jesús 32 , Labrador Espinosa 32 , C Lage 46 , A Legaz 34 , A Lleó 37 , A López de Munáin 47 , S López-García 46 , D Macias 32 , S Manzanares 48 , M Marín 36 , J Marín-Muñoz 34 , T Marín 14 , M Marquié 2 , A Martín Montes 49 , B Martínez 34 , C Martínez 50 , V Martínez 51 , P Martínez-Lage Álvarez 52 , M Medina 53 , M Mendioroz Iriarte 54 , M Menéndez-González 55 , P Mir 32 , J L Molinuevo 56 , G Monté-Rubio 2 , L Montrreal 2 , S Moreno-Grau 38 , A Orellana 2 , A B Pastor 57 , P Pastor 33 , J Pérez Tur 58 , T Periñán-Tocino 32 , G Piñol Ripoll 59 , A Rábano 60 , D Real de Asúa 61 , S Rodrigo 36 , E Rodríguez-Rodríguez 46 , J L Royo 15 , Ruiz A 38 , R Sanchez Del Valle Díaz 62 , P Sánchez-Juan 46 , I Sastre 63 , O Sotolongo-Grau 2 , L Tárraga 38 , S Valero 38 , M P Vicente 34 , L Vivancos 34
Affiliations
- 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.
- PMID: 31473137
- DOI: 10.1016/j.jalz.2019.06.4950
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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.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
