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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Published in:Molecular psychiatry Vol. 27; no. 4; pp. 1990 - 1999
Main Authors: 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
Language:English
Published: England Nature Publishing Group 01.04.2022
Subjects:
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 Access:Get full text
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Summary: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.
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ISSN:1359-4184
1476-5578
1476-5578
DOI:10.1038/s41380-022-01437-6