Integrative multi-omic analysis identifies new drivers and pathways in molecularly distinct subtypes of ALS

Abstract Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. Increasing the chances of success for future clinical strategies requires more in-depth knowledge of the molecular basis underlying disease heterogeneity. We recently laid the foundation for a molecular...

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Autores principales:	Giovanna Morello, Maria Guarnaccia, Antonio Gianmaria Spampinato, Salvatore Salomone, Velia D’Agata, Francesca Luisa Conforti, Eleonora Aronica, Sebastiano Cavallaro
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2c47732928ac47b9af5ea01a9f35d762
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spelling	oai:doaj.org-article:2c47732928ac47b9af5ea01a9f35d7622021-12-02T15:09:38ZIntegrative multi-omic analysis identifies new drivers and pathways in molecularly distinct subtypes of ALS10.1038/s41598-019-46355-w2045-2322https://doaj.org/article/2c47732928ac47b9af5ea01a9f35d7622019-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-46355-whttps://doaj.org/toc/2045-2322Abstract Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. Increasing the chances of success for future clinical strategies requires more in-depth knowledge of the molecular basis underlying disease heterogeneity. We recently laid the foundation for a molecular taxonomy of ALS by whole-genome expression profiling of motor cortex from sporadic ALS (SALS) patients. Here, we analyzed copy number variants (CNVs) occurring in the same patients, by using a customized exon-centered comparative genomic hybridization array (aCGH) covering a large panel of ALS-related genes. A large number of novel and known disease-associated CNVs were detected in SALS samples, including several subgroup-specific loci, suggestive of a great divergence of two subgroups at the molecular level. Integrative analysis of copy number profiles with their associated transcriptomic data revealed subtype-specific genomic perturbations and candidate driver genes positively correlated with transcriptional signatures, suggesting a strong interaction between genomic and transcriptomic events in ALS pathogenesis. The functional analysis confirmed our previous pathway-based characterization of SALS subtypes and identified 24 potential candidates for genomic-based patient stratification. To our knowledge, this is the first comprehensive “omics” analysis of molecular events characterizing SALS pathology, providing a road map to facilitate genome-guided personalized diagnosis and treatments for this devastating disease.Giovanna MorelloMaria GuarnacciaAntonio Gianmaria SpampinatoSalvatore SalomoneVelia D’AgataFrancesca Luisa ConfortiEleonora AronicaSebastiano CavallaroNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-18 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Giovanna Morello Maria Guarnaccia Antonio Gianmaria Spampinato Salvatore Salomone Velia D’Agata Francesca Luisa Conforti Eleonora Aronica Sebastiano Cavallaro Integrative multi-omic analysis identifies new drivers and pathways in molecularly distinct subtypes of ALS
description	Abstract Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease. Increasing the chances of success for future clinical strategies requires more in-depth knowledge of the molecular basis underlying disease heterogeneity. We recently laid the foundation for a molecular taxonomy of ALS by whole-genome expression profiling of motor cortex from sporadic ALS (SALS) patients. Here, we analyzed copy number variants (CNVs) occurring in the same patients, by using a customized exon-centered comparative genomic hybridization array (aCGH) covering a large panel of ALS-related genes. A large number of novel and known disease-associated CNVs were detected in SALS samples, including several subgroup-specific loci, suggestive of a great divergence of two subgroups at the molecular level. Integrative analysis of copy number profiles with their associated transcriptomic data revealed subtype-specific genomic perturbations and candidate driver genes positively correlated with transcriptional signatures, suggesting a strong interaction between genomic and transcriptomic events in ALS pathogenesis. The functional analysis confirmed our previous pathway-based characterization of SALS subtypes and identified 24 potential candidates for genomic-based patient stratification. To our knowledge, this is the first comprehensive “omics” analysis of molecular events characterizing SALS pathology, providing a road map to facilitate genome-guided personalized diagnosis and treatments for this devastating disease.
format	article
author	Giovanna Morello Maria Guarnaccia Antonio Gianmaria Spampinato Salvatore Salomone Velia D’Agata Francesca Luisa Conforti Eleonora Aronica Sebastiano Cavallaro
author_facet	Giovanna Morello Maria Guarnaccia Antonio Gianmaria Spampinato Salvatore Salomone Velia D’Agata Francesca Luisa Conforti Eleonora Aronica Sebastiano Cavallaro
author_sort	Giovanna Morello
title	Integrative multi-omic analysis identifies new drivers and pathways in molecularly distinct subtypes of ALS
title_short	Integrative multi-omic analysis identifies new drivers and pathways in molecularly distinct subtypes of ALS
title_full	Integrative multi-omic analysis identifies new drivers and pathways in molecularly distinct subtypes of ALS
title_fullStr	Integrative multi-omic analysis identifies new drivers and pathways in molecularly distinct subtypes of ALS
title_full_unstemmed	Integrative multi-omic analysis identifies new drivers and pathways in molecularly distinct subtypes of ALS
title_sort	integrative multi-omic analysis identifies new drivers and pathways in molecularly distinct subtypes of als
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/2c47732928ac47b9af5ea01a9f35d762
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Integrative multi-omic analysis identifies new drivers and pathways in molecularly distinct subtypes of ALS

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