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.

Autor:	Homann J; Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany., Osburg T; Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany., Ohlei O; Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany., Dobricic V; Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany., Deecke L; Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany., Bos I; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands.; Department of Neurology, Alzheimer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands., Vandenberghe R; Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.; Neurology Service, University Hospital Leuven, Leuven, Belgium., Gabel S; Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium., Scheltens P; Department of Neurology, Alzheimer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands., Teunissen CE; Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, Netherlands., Engelborghs S; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.; Department of Neurology and Center for Neurosciences, Universitair Ziekenhuis Brussel and Vrije Universiteit Brussel (VUB), Brussels, Belgium., Frisoni G; Department of Psychiatry, University of Geneva, Geneva, Switzerland.; IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy., Blin O; Institut Neurosciences Timone, AIX Marseille University, Marseille, France., Richardson JC; Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, United Kingdom., Bordet R; Lille Neuroscience and Cognition, University of Lille, Inserm, CHU Lille, Lille, France., Lleó A; Memory Unit, Neurology Department, Hospital de Sant Pau, Barcelona and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain., Alcolea D; Memory Unit, Neurology Department, Hospital de Sant Pau, Barcelona and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain., Popp J; Department of Geriatric Psychiatry, University Hospital of Psychiatry Zurich, Zurich, Switzerland.; Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland., Clark C; Department of Geriatric Psychiatry, University Hospital of Psychiatry Zurich, Zurich, Switzerland., Peyratout G; Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland., Martinez-Lage P; Department of Neurology, Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, Donostia-San Sebastian, Spain., Tainta M; Department of Neurology, Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, Donostia-San Sebastian, Spain., Dobson RJB; Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.; NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, United Kingdom.; Health Data Research UK London, University College London, London, United Kingdom.; Institute of Health Informatics, University College London, London, United Kingdom.; NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust, London, United Kingdom., Legido-Quigley C; Steno Diabetes Center, Copenhagen, Denmark.; King's College London, Institute of Pharmaceutical Sciences, London, United Kingdom., Sleegers K; Complex Genetics of Alzheimer's Disease Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium., Van Broeckhoven C; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.; Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium., Wittig M; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany., Franke A; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany., Lill CM; Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany.; Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, United Kingdom., Blennow K; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden., Zetterberg H; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, Queen Square, London, United Kingdom.; UK Dementia Research Institute at University College London, London, United Kingdom., Lovestone S; Department of Psychiatry, University of Oxford, Oxford, United Kingdom., Streffer J; Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.; Janssen R&D, LLC. Beerse, Belgium., Ten Kate M; Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.; Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, Netherlands., Vos SJB; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands., Barkhof F; Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, Netherlands.; Institutes of Neurology and Healthcare Engineering, University College London, London, United Kingdom., Visser PJ; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht University, Maastricht, Netherlands.; Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.; Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden., Bertram L; Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany.; Department of Psychology, University of Oslo, Oslo, Norway.
Jazyk:	angličtina
Zdroj:	Frontiers in aging neuroscience [Front Aging Neurosci] 2022 Mar 21; Vol. 14, pp. 840651. Date of Electronic Publication: 2022 Mar 21 (Print Publication: 2022).
DOI:	10.3389/fnagi.2022.840651
Abstrakt:	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. Competing Interests: HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and was a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which was a part of the GU Ventures Incubator Program. FB is supported by the NIHR biomedical research centre at UCLH. JP received consultation honoraria from Nestle Institute of Health Sciences, Ono Pharma, OM Pharma, and Fujirebio, unrelated to the submitted work. CT has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, PeopleBio, Roche, Toyama, Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology and Neuroinflammation, and was editor of a Neuromethods book Springer. CT also holds a speaker’s contract with Roche, Inc. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and was a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which was a part of the GU Ventures Incubator Program, outside the work presented in this paper. SL is currently an employee at Janssen Medical UK. JS was an employee of Janssen R&D, LLC., and is currently an employee and chief medical officer of AC Immune SA. JR was an employee of Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK. (Copyright © 2022 Homann, Osburg, Ohlei, Dobricic, Deecke, Bos, Vandenberghe, Gabel, Scheltens, Teunissen, Engelborghs, Frisoni, Blin, Richardson, Bordet, Lleó, Alcolea, Popp, Clark, Peyratout, Martinez-Lage, Tainta, Dobson, Legido-Quigley, Sleegers, Van Broeckhoven, Wittig, Franke, Lill, Blennow, Zetterberg, Lovestone, Streffer, ten Kate, Vos, Barkhof, Visser and Bertram.)
Databáze:	MEDLINE
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