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

Alexander Neumann ,Pieter Jelle Visser ,Stephanie J.b Vos ,Johannes Streffer ,Yvonne Freund‐Levi ,Ellen De Roeck ,Christine Van Broeckhoven ,Gwendoline Peyratout ,Lutz Frölich ,Mara Ten Kate ,Philip Scheltens ,Kristel Sleegers ,Pablo Martínez-Lage ,Magda Tsolaki ,Peter Johannsen ,О Блин ,Mikel Tainta ,Sebastiaan Engelborghs ,Simon Lovestone ,Geert Joris ,Peter De Rijk ,Giovanni B Frisoni ,Fahri Küçükali ,Tim De Pooter ,Lars Bertram ,Rik Vandenberghe ,Isabelle Bos ,Mojca Stražišar ,Cristina Legido‐Quigley ,Frederik Barkhof ,Henrik Zetterberg ,Julius Popp ,Jill C Richardson ,Frans R.j Verhey ,Régis Bordet ,Null Author_Id

doi:10.1038/s41380-022-01437-6

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.

Highlights

To further improve power and generalizability, we performed a Alzheimer’s disease (AD) is a neurodegenerative disease with an mega-analysis of two multi-center studies: the European Medical estimated heritability of 63% [1], with common variants Information Framework for Alzheimer’s Disease Multimodal explaining 9–31% of disease liability [2]
Both EMIF and as TREM2 mer’s Disease Neuroimaging Initiative (ADNI) represent an elderly population of comparable ages, but EMIF recruited a larger proportion of participants with AD
The second principal component (PC) loaded mostly on neurofilament light chain (NfL), with a moderate loading on YKL40, we can interpret it as indicating neuronal injury and inflammation

Summary

INTRODUCTION

To further improve power and generalizability, we performed a Alzheimer’s disease (AD) is a neurodegenerative disease with an mega-analysis of two multi-center studies: the European Medical estimated heritability of 63% [1], with common variants Information Framework for Alzheimer’s Disease Multimodal explaining 9–31% of disease liability [2]. We took a pathway approach by analyzing the ADNI proteomics data contained two peptide sequences, with two ion frequencies each, we averaged across these four values after z-score standardization. Both studies used the Mini-Mental State Examination, a 30 item questionnaire to assess dementia symptoms [28]. In EMIF we used the first four genome-wide PCs and in ADNI the first ten, taking into account the higher population admixture We performed analyses both with and without adjusting for diagnosis (dummy coding for MCI and AD), to avoid collider bias in case the genetic variant and PC are both independently causative of AD [35].

RESULTS

Neumann et al 5

DISCUSSION