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

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.

• Authors: Alexander Neumann, Fahri Küçükali, Isabelle Bos, Stephanie J B Vos, Sebastiaan Engelborghs, Tim De Pooter, Geert Joris, Peter De Rijk, Ellen De Roeck, Magda Tsolaki, Frans Verhey, Pablo Martinez-Lage, Mikel Tainta, Giovanni Frisoni, Oliver Blin, Jill Richardson, Régis Bordet, Philip Scheltens, Julius Popp, Gwendoline Peyratout, Peter Johannsen, Lutz Frölich, Rik Vandenberghe, Yvonne Freund-Levi, Johannes Streffer, Simon Lovestone, Cristina Legido-Quigley, Mara Ten Kate, Frederik Barkhof, Mojca Strazisar, Henrik Zetterberg, Lars Bertram, Pieter Jelle Visser, Christine van Broeckhoven, Kristel Sleegers, EMIF-AD study group
• Journal: Molecular psychiatry (Mol Psychiatry) Vol. 27 Issue 4 Pg. 1990-1999 (04 2022) ISSN: 1476-5578 [Electronic] England
• PMID: 35173266 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2022. The Author(s).

Chemical References

• Amyloid beta-Peptides
• Biomarkers
• CASZ1 protein, human
• Chitinase-3-Like Protein 1
• DNA-Binding Proteins
• Intercellular Signaling Peptides and Proteins
• NLRC3 protein, human
• Transcription Factors
• tau Proteins
• Neurogranin
• Dithionitrobenzoic Acid

Topics

• Alzheimer Disease (diagnosis)
• Amyloid beta-Peptides (genetics)
• Biomarkers
• Chitinase-3-Like Protein 1 (genetics)
• DNA-Binding Proteins
• Dithionitrobenzoic Acid
• Humans
• Inflammation (genetics)
• Intercellular Signaling Peptides and Proteins
• Neurogranin (genetics)
• Transcription Factors
• tau Proteins