Scelsi, M;
Napolioni, V;
Greicius, M;
Altmann, A;
(2021)
Network propagation of rare variants in Alzheimer’s disease reveals tissue-specific hub genes and communities.
PLOS Computational Biology
, 17
(1)
, Article e1008517. 10.1371/journal.pcbi.1008517.
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Abstract
State-of-the-art rare variant association testing methods aggregate the contribution of rare variants in biologically relevant genomic regions to boost statistical power. However, testing single genes separately does not consider the complex interaction landscape of genes, nor the downstream effects of non-synonymous variants on protein structure and function. Here we present the NETwork Propagation-based Assessment of Genetic Events (NETPAGE), an integrative approach aimed at investigating the biological pathways through which rare variation results in complex disease phenotypes. We applied NETPAGE to sporadic, late-onset Alzheimer’s disease (AD), using whole-genome sequencing from the AD Neuroimaging Initiative (ADNI) cohort, as well as whole-exome sequencing from the AD Sequencing Project (ADSP). NETPAGE is based on network propagation, a framework that models information flow on a graph and simulates the percolation of genetic variation through tissue-specific gene interaction networks. The result of network propagation is a set of smoothed gene scores that can be tested for association with disease status through sparse regression. The application of NETPAGE to AD enabled the identification of a set of connected genes whose smoothed variation profile was robustly associated to case-control status, based on gene interactions in the hippocampus. Additionally, smoothed scores significantly correlated with risk of conversion to AD in Mild Cognitive Impairment (MCI) subjects. Lastly, we investigated tissue-specific transcriptional dysregulation of the core genes in two independent RNA-seq datasets, as well as significant enrichments in terms of gene sets with known connections to AD. We present a framework that enables enhanced genetic association testing for a wide range of traits, diseases, and sample sizes.
| Type: | Article |
|---|---|
| Title: | Network propagation of rare variants in Alzheimer’s disease reveals tissue-specific hub genes and communities |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pcbi.1008517 |
| Publisher version: | https://doi.org/10.1371/journal.pcbi.1008517 |
| Language: | English |
| Additional information: | © 2021 Scelsi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| Keywords: | gene networks, rare variants, Alzheimer’s disease, network propagation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10116159 |
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