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Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation
Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Netherlands Institute for Health Services Research, Utrecht, the Netherlands.
Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands.
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2022 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, no 4, p. 1990-1999Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer Nature, 2022. Vol. 27, no 4, p. 1990-1999
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Neurosciences
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URN: urn:nbn:se:oru:diva-97581DOI: 10.1038/s41380-022-01437-6ISI: 000756220100002PubMedID: 35173266Scopus ID: 2-s2.0-85127021020OAI: oai:DiVA.org:oru-97581DiVA, id: diva2:1639045
Funder
EU, FP7, Seventh Framework ProgrammeSwedish Research Council, 2018-02532EU, European Research Council, 681712Stiftelsen Gamla Tjänarinnor, FO2019-0228The Swedish Brain FoundationEU, Horizon 2020, 860197Pfizer ABAvailable from: 2022-02-18 Created: 2022-02-18 Last updated: 2023-12-08Bibliographically approved

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Freund-Levi, Yvonne

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