Network propagation of rare variants in Alzheimer's disease reveals tissue-specific hub genes and communities.

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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Marzia Antonella Scelsi, Valerio Napolioni, Michael D Greicius, Andre Altmann, Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Alzheimer’s Disease Sequencing Project (ADSP)
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/854d9beab71e40a09f04f3efa6b2cb6f
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:854d9beab71e40a09f04f3efa6b2cb6f
record_format	dspace
spelling	oai:doaj.org-article:854d9beab71e40a09f04f3efa6b2cb6f2021-12-02T19:57:26ZNetwork propagation of rare variants in Alzheimer's disease reveals tissue-specific hub genes and communities.1553-734X1553-735810.1371/journal.pcbi.1008517https://doaj.org/article/854d9beab71e40a09f04f3efa6b2cb6f2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1008517https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358State-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.Marzia Antonella ScelsiValerio NapolioniMichael D GreiciusAndre AltmannAlzheimer’s Disease Neuroimaging Initiative (ADNI) and the Alzheimer’s Disease Sequencing Project (ADSP)Public Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 1, p e1008517 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Marzia Antonella Scelsi Valerio Napolioni Michael D Greicius Andre Altmann Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Alzheimer’s Disease Sequencing Project (ADSP) Network propagation of rare variants in Alzheimer's disease reveals tissue-specific hub genes and communities.
description	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.
format	article
author	Marzia Antonella Scelsi Valerio Napolioni Michael D Greicius Andre Altmann Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Alzheimer’s Disease Sequencing Project (ADSP)
author_facet	Marzia Antonella Scelsi Valerio Napolioni Michael D Greicius Andre Altmann Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Alzheimer’s Disease Sequencing Project (ADSP)
author_sort	Marzia Antonella Scelsi
title	Network propagation of rare variants in Alzheimer's disease reveals tissue-specific hub genes and communities.
title_short	Network propagation of rare variants in Alzheimer's disease reveals tissue-specific hub genes and communities.
title_full	Network propagation of rare variants in Alzheimer's disease reveals tissue-specific hub genes and communities.
title_fullStr	Network propagation of rare variants in Alzheimer's disease reveals tissue-specific hub genes and communities.
title_full_unstemmed	Network propagation of rare variants in Alzheimer's disease reveals tissue-specific hub genes and communities.
title_sort	network propagation of rare variants in alzheimer's disease reveals tissue-specific hub genes and communities.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/854d9beab71e40a09f04f3efa6b2cb6f
work_keys_str_mv	AT marziaantonellascelsi networkpropagationofrarevariantsinalzheimersdiseaserevealstissuespecifichubgenesandcommunities AT valerionapolioni networkpropagationofrarevariantsinalzheimersdiseaserevealstissuespecifichubgenesandcommunities AT michaeldgreicius networkpropagationofrarevariantsinalzheimersdiseaserevealstissuespecifichubgenesandcommunities AT andrealtmann networkpropagationofrarevariantsinalzheimersdiseaserevealstissuespecifichubgenesandcommunities AT alzheimersdiseaseneuroimaginginitiativeadniandthealzheimersdiseasesequencingprojectadsp networkpropagationofrarevariantsinalzheimersdiseaserevealstissuespecifichubgenesandcommunities
_version_	1718375850068410368

Network propagation of rare variants in Alzheimer's disease reveals tissue-specific hub genes and communities.

Ejemplares similares