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| Pàgina inicial > Articles > Articles publicats > Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset |
(Neurology Service. University Hospital Leuven) (Vrije Universiteit Amsterdam) (Vrije Universiteit Amsterdam) (Vrije Universiteit Amsterdam) (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Old Age Psychiatry. Department of Psychiatry. University Hospital of Lausanne) (Department of Geriatric Psychiatry. University Hospital of Psychiatry Zurich) (Department of Neurology. Center for Research and Advanced Therapies. CITA-Alzheimer Foundation) (Department of Neurology. Center for Research and Advanced Therapies. CITA-Alzheimer Foundation) (King's College London. Institute of Pharmaceutical Sciences) (Center for Molecular Neurology) (University of Antwerp) (Christian-Albrechts-University of Kiel. Institute of Clinical Molecular Biology) (Sahlgrenska University Hospital (Suècia)) (University College London. UK Dementia Research Institute) (University of Oxford. Department of Psychiatry) (University College London) (University of Oslo)
| Data: | 2022 |
| Resum: | Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i. e. , case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24. 1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21. 3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline. |
| Ajuts: | European Commission 115372 European Commission 116020 European Commission 860197 European Commission 116074 European Commission JPND2019-466-236 |
| Nota: | Altres ajuts: German Research Foundation (DFG grant FOR2488: Main support by subproject "INF-GDAC" BE2287/7-1); Cure Alzheimer's Fund; Stichting Alzheimer Onderzoek (#13007, #11020, #2017-032); Flemish Government (VIND IWT 135043); Swedish Research Council (#2017-00915); Alzheimer Drug Discovery Foundation (ADDF), United States (#RDAPB-201809-2016615); Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243); Swedish Government and the County Councils, the ALF-agreement (#ALFGBG-715986); Alzheimer's Association 2021 Zenith Award (ZEN-21-848495); Swedish Research Council (#2018-02532), Swedish State Support for Clinical Research (#ALFGBG-720931); ZonMw; University of Antwerp Research Fund (SAO-FRA 2018 0016); Swiss National Research Foundation (SNF 320030_141179); Health Holland; Dutch Research Council (ZonMW); Alzheimer Drug Discovery Foundation; Selfridges Group Foundation; Alzheimer Netherlands; Alzheimer Association; ZonMW (#73305095007); Health-Holland, Topsector Life Sciences and Health (PPP-allowance; #LSHM20106); Edwin Bouw Fonds; Gieskes-Strijbisfonds; NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, United Kingdom; UK Medical Research Council; Engineering and Physical Sciences Research Council; Economic and Social Research Council; Department of Health and Social Care (England); Chief Scientist Office of the Scottish Government; Health and Social Care Directorates; Health and Social Care Research and Development Division (Welsh Government); Public Health Agency (Northern Ireland); British Heart Foundation and Wellcome Trust; European Union's Horizon 2020 Research and Innovation Programme and EFPIA; National Institute for Health Research University College London Hospitals Biomedical Research Centre; National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London; UK Research and Innovation London Medical Imaging and Artificial Intelligence Centre for Value-Based Healthcare; National Institute for Health Research (NIHR) Applied Research Collaboration South London (NIHR ARC South London) at King's College Hospital NHS Foundation Trust; Land Schleswig-Holstein within the funding programme Open Access Publikationsförderung. |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Genome-wide association study ; GWAS ; X chromosome ; Alzheimer's disease (AD) ; MRI ; Imaging ; Cognitive function |
| Publicat a: | Frontiers in aging neuroscience, Vol. 14 (March 2022) , p. 840651, ISSN 1663-4365 |
