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

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 (β-amyloid, total/phosphorylated tau, NfL, YKL-4...

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Veröffentlicht in:Molecular psychiatry Jg. 27; H. 4; S. 1990 - 1999
Hauptverfasser: Neumann, Alexander, Küçükali, Fahri, Bos, Isabelle, Vos, Stephanie J B, Engelborghs, Sebastiaan, De Pooter, Tim, Joris, Geert, De Rijk, Peter, De Roeck, Ellen, Tsolaki, Magda, Verhey, Frans, Martinez-Lage, Pablo, Tainta, Mikel, Frisoni, Giovanni, Blin, Oliver, Richardson, Jill, Bordet, Régis, Scheltens, Philip, Popp, Julius, Peyratout, Gwendoline, Johannsen, Peter, Frölich, Lutz, Vandenberghe, Rik, Freund-Levi, Yvonne, Streffer, Johannes, Lovestone, Simon, Legido-Quigley, Cristina, Ten Kate, Mara, Barkhof, Frederik, Strazisar, Mojca, Zetterberg, Henrik, Bertram, Lars, Visser, Pieter Jelle, van Broeckhoven, Christine, Sleegers, Kristel
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Nature Publishing Group 01.04.2022
Schlagworte:
Alzheimer Disease - diagnosis
Alzheimer's disease
Amyloid beta-Peptides - genetics
Biomarkers
Cerebrospinal fluid
Chitinase-3-Like Protein 1 - genetics
Cytoskeleton
Dementia
Dementia disorders
Dithionitrobenzoic Acid
DNA-Binding Proteins
Humans
Inflammation
Inflammation - genetics
Intercellular Signaling Peptides and Proteins
Neural coding
Neurodegenerative diseases
Neurogranin
Neurogranin - genetics
Tau protein
tau Proteins
Transcription Factors
β-Amyloid
ISSN:1359-4184, 1476-5578, 1476-5578
Online-Zugang:Volltext
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Abstract 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 (β-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.
AbstractList 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 (β-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.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 (β-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.
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 (β-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.
Author van Broeckhoven, Christine
Streffer, Johannes
Engelborghs, Sebastiaan
Frisoni, Giovanni
Peyratout, Gwendoline
De Rijk, Peter
Joris, Geert
Legido-Quigley, Cristina
Bos, Isabelle
Johannsen, Peter
Frölich, Lutz
De Pooter, Tim
Tsolaki, Magda
Barkhof, Frederik
Verhey, Frans
Bordet, Régis
Blin, Oliver
Zetterberg, Henrik
Bertram, Lars
Strazisar, Mojca
Sleegers, Kristel
Vos, Stephanie J B
Ten Kate, Mara
Freund-Levi, Yvonne
Visser, Pieter Jelle
Küçükali, Fahri
Richardson, Jill
Neumann, Alexander
Tainta, Mikel
De Roeck, Ellen
Martinez-Lage, Pablo
Popp, Julius
Vandenberghe, Rik
Lovestone, Simon
Scheltens, Philip
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/35173266$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Contributor van Broeckhoven, Christine
Streffer, Johannes
Engelborghs, Sebastiaan
Frisoni, Giovanni
Peyratout, Gwendoline
Legido-Quigley, Cristina
Bos, Isabelle
Johannsen, Peter
Frölich, Lutz
Tsolaki, Magda
Barkhof, Frederik
Verhey, Frans
Bordet, Régis
Blin, Oliver
Zetterberg, Henrik
Bertram, Lars
Sleegers, Kristel
Vos, Stephanie J B
Ten Kate, Mara
Freund-Levi, Yvonne
Visser, Pieter Jelle
Küçükali, Fahri
Richardson, Jill
Neumann, Alexander
Tainta, Mikel
De Roeck, Ellen
Martinez-Lage, Pablo
Popp, Julius
Vandenberghe, Rik
Lovestone, Simon
Scheltens, Philip
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Copyright_xml – notice: 2022. The Author(s).
– notice: The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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PublicationTitle Molecular psychiatry
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Snippet Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as...
Alzheimer’s disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as...
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SubjectTerms Alzheimer Disease - diagnosis
Alzheimer's disease
Amyloid beta-Peptides - genetics
Biomarkers
Cerebrospinal fluid
Chitinase-3-Like Protein 1 - genetics
Cytoskeleton
Dementia
Dementia disorders
Dithionitrobenzoic Acid
DNA-Binding Proteins
Humans
Inflammation
Inflammation - genetics
Intercellular Signaling Peptides and Proteins
Neural coding
Neurodegenerative diseases
Neurogranin
Neurogranin - genetics
Tau protein
tau Proteins
Transcription Factors
β-Amyloid
Title Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation
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Volume 27
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