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

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. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.The authors would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Fundacion bancaria "La Caixa", Grifols SA, Fundacio 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 Fundacio ACE). They are indebted to the Trinitat Port-Carbo legacy and her family for their support of Fundacio ACE research programs. Fundacio 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. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-"Una manera de Hacer Europa"). L.M.R. is supported by Consejeria de Salud de la Junta de Andalucia (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. MorenoGrau at Universitat Autonoma 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 K1oszewska (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 Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilufer 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 collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, and R01 AG003949, NINDS grant R01 NS080820, the CurePSP Foundation, and support from the Mayo Foundation. The Neocodex-Murcia study was funded by the Fundacion Alzheimur (Murcia), the Ministerio de Educacion y Ciencia (Gobierno de Espana), Corporacion Tecnologica de Andalucia, Agencia IDEA (Consejeria de Innovacion, Junta de Andalucia), the Diabetes Research Laboratory, and the Biomedical Research Foundation. University Hospital Clinico San Carlos has been supported by CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM); CIBERDEM is an ISCIII Project. The ROS/MAP study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984 and U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute. The TGEN study was supported by Kronos Life Science Laboratories, the National Institute on Aging (Arizona Alzheimer's Disease Center grants P30 AG19610 and RO1 AG023193, the Mayo Clinic Alzheimer's Disease Center grant P50 AG16574, and the Intramural Research Program), the National Alzheimer's Coordinating Center (U01 AG016976), and the state of Arizona. The authors thank the International Genomics of Alzheimer's Project (IGAP) for providing summary result data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chip was funded by the French National Foundation on Alzheimer's disease and related disorders. European Alzheimer's Disease Initiative (EADI) was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Universite de Lille 2, and the Lille University Hospital. GERAD was supported by the Medical Research Council (grant no. 503480), Alzheimer's Research UK (grant no. 503176), the Wellcome Trust (grant no. 082604/2/07/Z), and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no. 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01-AG12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC-10-196728