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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 GRaACE project.

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dc.contributor.authorMoreno-Grau, Sonia
dc.contributor.authorde Rojas, Itziar
dc.contributor.authorHernández, Isabel
dc.contributor.authorQuintela, Inés
dc.contributor.authorMontrreal, Laura
dc.contributor.authorAlegret, Montserrat
dc.contributor.authorHernández-Olasagarre, Begoña
dc.contributor.authorMadrid, Laura
dc.contributor.authorGonzález-Pérez, Antonio
dc.contributor.authorMaroñas, Olalla
dc.contributor.authorRosende-Roca, Maitée
dc.contributor.authorMauleón, Ana
dc.contributor.authorVargas, Liliana
dc.contributor.authorLafuente, Asunción
dc.contributor.authorAbdelnour, Carla
dc.contributor.authorRodríguez-Gómez, Octavio
dc.contributor.authorGil, Silvia
dc.contributor.authorSantos-Santos, Miguel Ángel
dc.contributor.authorEspinosa, Ana
dc.contributor.authorOrtega, Gemma
dc.contributor.authorSanabria, Ángela
dc.contributor.authorPérez-Cordón, Alba
dc.contributor.authorCañabate, Pilar
dc.contributor.authorMoreno, Mariola
dc.contributor.authorPreckler, Silvia
dc.contributor.authorRuiz, Susana
dc.contributor.authorAguilera, Nuria
dc.contributor.authorPineda, Juan Antonio
dc.contributor.authorMacías, Juan
dc.contributor.authorAlarcón-Martín, Emilio
dc.contributor.authorSotolongo-Grau, Oscar
dc.contributor.authorMarquié, Marta
dc.contributor.authorMonté-Rubio, Gemma
dc.contributor.authorValero, Sergi
dc.contributor.authorBenaque, Alba
dc.contributor.authorClarimón, Jordi
dc.contributor.authorBullido, María Jesús
dc.contributor.authorGarcia-Ribas, Guillermo
dc.contributor.authorPástor, Pau
dc.contributor.authorSánchez-Juan, Pascual
dc.contributor.authorÁlvarez, Victoria
dc.contributor.authorPiñol-Ripoll, Gerard
dc.contributor.authorGarcía-Alberca, Jose María
dc.contributor.authorRoyo, José Luis
dc.contributor.authorFranco, Emilio
dc.contributor.authorMir, Pablo
dc.contributor.authorCalero, Miguel
dc.contributor.authorMedina, Miguel
dc.contributor.authorRábano, Alberto
dc.contributor.authorÁvila, Jesús
dc.contributor.authorAntúnez, Carmen
dc.contributor.authorReal, Luis Miguel
dc.contributor.authorOrellana, Adelina
dc.contributor.authorCarracedo, Ángel
dc.contributor.authorSáez, María Eugenia
dc.contributor.authorTárraga, Lluís
dc.contributor.authorBoada, Mercè
dc.contributor.authorRuiz, Agustín
dc.contributor.funderFundación La Caixa
dc.contributor.funderGrifols (Spain)
dc.contributor.funderFundació ACE
dc.contributor.funderInstituto de Salud Carlos III
dc.contributor.funderMinisterio de Sanidad (España)
dc.contributor.funderUnión Europea
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
dc.contributor.funderRegional Government of Andalusia (España)
dc.contributor.funderNational Institutes of Health (Estados Unidos)
dc.contributor.funderUnited States Department of Defense
dc.contributor.funderNIH - National Institute on Aging (NIA) (Estados Unidos)
dc.contributor.funderNIH - National Institute of Biomedical Imaging and Bioengineering (NIBIB) (Estados Unidos)
dc.contributor.funderInnovative Medicines Initiative
dc.contributor.funderUnión Europea. Comisión Europea. 6 Programa Marco
dc.contributor.funderAlzheimer's Disease Genetics Consortium
dc.date.accessioned2021-04-27T15:23:30Z
dc.date.available2021-04-27T15:23:30Z
dc.date.issued2019
dc.description.abstractIntroduction: 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.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipThe authors would like to thank patients and controls who participated in this project. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Fundación bancaria “La Caixa”, Grifols SA, Fundació ACE, and ISCIII (Ministry of Health, Spain). They also want to thank the private sponsors who support the basic and clinical projects of our institution (Piramal AG, Laboratorios Echevarne, Araclon Biotech S.A., and Fundació ACE). They are indebted to the Trinitat Port‐Carbó legacy and her family for their support of Fundació ACE research programs. Fundació ACE is a participating center in the Dementia Genetics Spanish Consortium (DEGESCO). A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, and PI17/01474. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)‐Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER‐ “Una manera de Hacer Europa”). L.M.R. is supported by Consejería de Salud de la Junta de Andalucía (grant PI‐0001/2017). Control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed after standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. The present work was performed as part of the Biochemistry, Molecular Biology, and Biomedicine doctoral program of S. Moreno‐Grau at Universitat Autònoma de Barcelona (Barcelona, Spain). Data collection and sharing for this project was partially funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH‐12–2–0012). The ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering, as well as through generous contributions from the following: AbbVie; the Alzheimer's Association; the Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study was coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. The AddNeuroMed data are from a public‐private partnership supported by EFPIA companies and SMEs as part of InnoMed (Innovative Medicines in Europe), an integrated project funded by the European Union of the Sixth Framework program priority FP6–2004‐LIFESCIHEALTH‐5. Clinical leads responsible for data collection are Iwona Kłoszewska (Lodz), Simon Lovestone (London), Patrizia Mecocci (Perugia), Hilkka Soininen (Kuopio), Magda Tsolaki (Thessaloniki), and Bruno Vellas (Toulouse). Imaging leads are Andy Simmons (London), Lars‐Olad Wahlund (Stockholm), and Christian Spenger (Zurich). Bioinformatics leads are Richard Dobson (London) and Stephen Newhouse (London). Funding support for the Alzheimer's Disease Genetics Consortium (ADGC) was provided through the NIA Division of Neuroscience (U01‐AG032984). The genotypic and associated phenotypic data used in the study “Multi‐Site Collaborative Study for Genotype‐Phenotype Associations in Alzheimer's Disease (GenADA)” were provided by GlaxoSmithKline, R&D Limited. The data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000219. The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilüfer Ertekin‐Taner and Dr. Steven G. Younkin at the Mayo Clinic in Jacksonville, FL, used samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data ces_ES
dc.format.number10es_ES
dc.format.page1333-1347es_ES
dc.format.volume15es_ES
dc.identifier.citationMoreno-Grau S, De Rojas I, Hernandez I, Quintela I, Montrreal L, Alegret M, et al. 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. Alzheimers Dement. 2019 Oct;15(10):1333-47.es_ES
dc.identifier.doi10.1016/j.jalz.2019.06.4950es_ES
dc.identifier.e-issn1552-5279es_ES
dc.identifier.journalAlzheimer's & dementia : the journal of the Alzheimer's Associationes_ES
dc.identifier.otherhttp://hdl.handle.net/20.500.13003/17141
dc.identifier.pubmedID31473137es_ES
dc.identifier.puiL2003282292
dc.identifier.scopus2-s2.0-85072869719
dc.identifier.urihttp://hdl.handle.net/20.500.12105/12785
dc.identifier.wos490148500009
dc.language.isoenges_ES
dc.publisherWiley
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PI13/02434es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PI16/01861,es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/PI17/01474es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/115975es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/115985es_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.jalz.2019.06.4950es_ES
dc.repisalud.centroISCIII::Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)es_ES
dc.repisalud.institucionISCIIIes_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAlzheimer's diseasees_ES
dc.subjectBiological pathwayes_ES
dc.subjectCerebral amyloid angiopathyes_ES
dc.subjectGWASes_ES
dc.subjectVascular pathologyes_ES
dc.subject.decsPolimorfismo de Nucleótido Simple
dc.subject.decsPredisposición Genética a la Enfermedad
dc.subject.decsFemenino
dc.subject.decsMasculino
dc.subject.decsSitios Genéticos
dc.subject.decsEstudio de Asociación del Genoma Completo
dc.subject.decsHumanos
dc.subject.decsPersona de Mediana Edad
dc.subject.decsAnciano
dc.subject.decsEnfermedad de Alzheimer
dc.subject.decsEndofenotipos
dc.subject.decsDemencia
dc.subject.decsEspaña
dc.subject.meshEndophenotypeses_ES
dc.subject.meshGenetic Locies_ES
dc.subject.meshGenome-Wide Association Studyes_ES
dc.subject.meshAgedes_ES
dc.subject.meshAlzheimer Diseasees_ES
dc.subject.meshDementiaes_ES
dc.subject.meshFemalees_ES
dc.subject.meshGenetic Predisposition to Diseasees_ES
dc.subject.meshHumanses_ES
dc.subject.meshMalees_ES
dc.subject.meshMiddle Agedes_ES
dc.subject.meshPolymorphism, Single Nucleotidees_ES
dc.subject.meshSpaines_ES
dc.titleGenome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GRaACE project.es_ES
dc.typeresearch articlees_ES
dc.type.hasVersionVoRes_ES
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IBIS - Instituto de Biomedicina de Sevilla (Andalucía)
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