Sonia Moreno-Grau1, Itziar de Rojas2, Isabel Hernández1, Inés Quintela3, Laura Montrreal2, Montserrat Alegret1, Begoña Hernández-Olasagarre2, Laura Madrid4, Antonio González-Perez4, Olalla Maroñas3, Maitée Rosende-Roca2, Ana Mauleón2, Liliana Vargas2, Asunción Lafuente2, Carla Abdelnour1, Octavio Rodríguez-Gómez1, Silvia Gil2, Miguel Ángel Santos-Santos2, Ana Espinosa1, Gemma Ortega1, Ángela Sanabria1, Alba Pérez-Cordón2, Pilar Cañabate1, Mariola Moreno2, Silvia Preckler2, Susana Ruiz1, Nuria Aguilera2, Juan Antonio Pineda5, Juan Macías5, Emilio Alarcón-Martín6, Oscar Sotolongo-Grau2, Marta Marquié2, Gemma Monté-Rubio2, Sergi Valero1, Alba Benaque2, Jordi Clarimón7, Maria Jesus Bullido8, Guillermo García-Ribas9, Pau Pástor10, Pascual Sánchez-Juan11, Victoria Álvarez12, Gerard Piñol-Ripoll13, Jose Maria García-Alberca14, José Luis Royo15, Emilio Franco16, Pablo Mir17, Miguel Calero18, Miguel Medina19, Alberto Rábano20, Jesús Ávila21, Carmen Antúnez22, Luis Miguel Real23, Adelina Orellana2, Ángel Carracedo24, María Eugenia Sáez4, Lluís Tárraga1, Mercè Boada1, Agustín Ruiz25. 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.
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.
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.
Authors: Sarah L Morgan; Pourya Naderi; Katjuša Koler; Yered Pita-Juarez; Dmitry Prokopenko; Ioannis S Vlachos; Rudolph E Tanzi; Lars Bertram; Winston A Hide Journal: Front Aging Neurosci Date: 2022-06-24 Impact factor: 5.702