Koçoğlu, Cemile;
Ferrari, Raffaele;
Roes, Maxime;
Vandeweyer, Geert;
Kooy, R Frank;
van Broeckhoven, Christine;
Manzoni, Claudia;
(2022)
Protein interaction network analysis reveals genetic enrichment of immune system genes in frontotemporal dementia.
Neurobiology of Aging
10.1016/j.neurobiolaging.2022.03.018.
(In press).
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Abstract
To further unravel the complex genetic etiology of frontotemporal dementia (FTD), we hypothesized that interactors of the protein products of known FTD genes might be involved in the molecular pathways towards disease. We therefore applied protein interaction network (PIN) analysis to prioritize candidate genes for rare variant association. We created an FTD-PIN starting from known FTD genes downloading their physical interactors and performed functional enrichment analyses. We identified overrepresented processes in FTD and selected genes (n=440) belonging to the FTD processes for rare variant analysis in a Belgian cohort of 228 FTD patients and 345 controls. SKAT-O analysis suggested TNFAIP3 as the top gene (P = 0.7 × 10−3) reaching near test-wide significance (P = 2.5 × 10−4). We then analyzed the TNFAIP3-subnetwork within the FTD-PIN which indicated enrichment of several immune signaling networks, suggesting that disrupted immune signaling may be implicated in TNFAIP3-related FTD. Our study demonstrates that integration of PINs with genetic data is a useful approach to increase the power for rare variant association analysis. Furthermore, we present a computational pipeline for identifying potential novel therapeutic targets and risk-modifying variants.
| Type: | Article |
|---|---|
| Title: | Protein interaction network analysis reveals genetic enrichment of immune system genes in frontotemporal dementia |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.neurobiolaging.2022.03.018 |
| Publisher version: | https://doi.org/10.1016/j.neurobiolaging.2022.03.0... |
| Language: | English |
| Additional information: | © 2022 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
| Keywords: | protein-protein interaction network, rare variant association analysis, frontotemporal dementia, candidate gene prioritization |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10147062 |
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