Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation

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Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation

Neumann, A. (författare): Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

Kucukali, F. (författare): Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

Bos, I. (författare): Netherlands Institute for Health Services Research, Utrecht, the Netherlands

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Vos, S. J. B. (författare): Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands,Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

Engelborghs, S. (författare): Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Universitair Ziekenhuis Brussel (UZ Brussel) and Center for Neurosciences (C4N), Vrije Universiteit Brussel (VUB), Brussels, Belgium

De Pooter, T. (författare): Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Neuromics Support Facility, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Joris, G. (författare): Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Neuromics Support Facility, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

De Rijk, P. (författare): Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium

De Roeck, E. (författare): Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium

Tsolaki, M. (författare): 1st Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Makedonia, Thessaloniki, Greece

Verhey, F. (författare): Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands; School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain

Martinez-Lage, P. (författare): Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain

Tainta, M. (författare): Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain

Frisoni, G. (författare): Department of Psychiatry, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland; RCCS Instituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy

Blin, O. (författare): Clinical Pharmacology & Pharmacovigilance Department, Marseille University Hospital, Marseille, France

Richardson, J. (författare): Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevanage, UK

Bordet, R. (författare): Neuroscience & Cognition, CHU de Lille, University of Lille, Inserm, France

Scheltens, P. (författare): Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands

Popp, J. (författare): Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich, Zürich, Switzerland; Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland

Peyratout, G. (författare): Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland

Johannsen, P. (författare): Clinical Drug Development, Novo Nordisk, Copenhagen, Denmark

Frolich, L. (författare): Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

Vandenberghe, R. (författare): Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium

Freund-Levi, Yvonne, 1956- (författare): Örebro universitet,Institutionen för medicinska vetenskaper,Center for Alzheimer Research, Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society Karolinska Institute Stockholm Sweden, Stockholm, Sweden

Streffer, J. (författare)

Lovestone, S. (författare): Department of Psychiatry, University of Oxford, Oxford, UK; Janssen Medical Ltd, High Wycombe, UK

Legido-Quigley, C. (författare): Steno Diabetes Center, Copenhagen, Denmark; Institute of Pharmaceutical Sciences, King's College London, London, UK

ten Kate, M. (författare): Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands; Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands

Barkhof, F. (författare): Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands; Institutes of Neurology and Healthcare Engineering, University College London, London, UK

Strazisar, M. (författare): Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Neuromics Support Facility, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Zetterberg, Henrik, 1973 (författare): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry,Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute, University College London, London, UK; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China

Bertram, L. (författare): Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany; Centre for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo, Norway

Visser, P. J. (författare): Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands; Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands

van Broeckhoven, C. (författare): Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium

Sleegers, K. (författare): Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

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2022-02-16
2022
Engelska.
Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27

Relaterad länk:: https://www.nature.c...; visa fler...; https://doi.org/10.1...; https://gup.ub.gu.se...; https://doi.org/10.1...; https://urn.kb.se/re...; http://kipublication...; visa färre...

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Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (beta-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on NfL and YKL-40, indicators of neuronal injury and inflammation. Four genes were associated with this PC: IFFO1, DTNB, NLRC3, and SLC22A10. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB, NLRC3, and SLC22A10 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development.

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Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation

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