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An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients

Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease’s estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italia...

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Autores principales: Barizzone, Nadia, Cagliani, Rachele, Basagni, Chiara, Clarelli, Ferdinando, Mendozzi, Laura, Agliardi, Cristina, Forni, Diego, Tosi, Martina, Mascia, Elisabetta, Favero, Francesco, Corà, Davide, Corrado, Lucia, Sorosina, Melissa, Esposito, Federica, Zuccalà, Miriam, Vecchio, Domizia, Liguori, Maria, Comi, Cristoforo, Comi, Giancarlo, Martinelli, Vittorio, Filippi, Massimo, Leone, Maurizio, Martinelli-Boneschi, Filippo, Caputo, Domenico, Sironi, Manuela, Guerini, Franca Rosa, D’Alfonso, Sandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535321/
https://www.ncbi.nlm.nih.gov/pubmed/34681001
http://dx.doi.org/10.3390/genes12101607
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author Barizzone, Nadia
Cagliani, Rachele
Basagni, Chiara
Clarelli, Ferdinando
Mendozzi, Laura
Agliardi, Cristina
Forni, Diego
Tosi, Martina
Mascia, Elisabetta
Favero, Francesco
Corà, Davide
Corrado, Lucia
Sorosina, Melissa
Esposito, Federica
Zuccalà, Miriam
Vecchio, Domizia
Liguori, Maria
Comi, Cristoforo
Comi, Giancarlo
Martinelli, Vittorio
Filippi, Massimo
Leone, Maurizio
Martinelli-Boneschi, Filippo
Caputo, Domenico
Sironi, Manuela
Guerini, Franca Rosa
D’Alfonso, Sandra
author_facet Barizzone, Nadia
Cagliani, Rachele
Basagni, Chiara
Clarelli, Ferdinando
Mendozzi, Laura
Agliardi, Cristina
Forni, Diego
Tosi, Martina
Mascia, Elisabetta
Favero, Francesco
Corà, Davide
Corrado, Lucia
Sorosina, Melissa
Esposito, Federica
Zuccalà, Miriam
Vecchio, Domizia
Liguori, Maria
Comi, Cristoforo
Comi, Giancarlo
Martinelli, Vittorio
Filippi, Massimo
Leone, Maurizio
Martinelli-Boneschi, Filippo
Caputo, Domenico
Sironi, Manuela
Guerini, Franca Rosa
D’Alfonso, Sandra
author_sort Barizzone, Nadia
collection PubMed
description Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease’s estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes—particularly mRNA transport—or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family.
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spelling pubmed-85353212021-10-23 An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients Barizzone, Nadia Cagliani, Rachele Basagni, Chiara Clarelli, Ferdinando Mendozzi, Laura Agliardi, Cristina Forni, Diego Tosi, Martina Mascia, Elisabetta Favero, Francesco Corà, Davide Corrado, Lucia Sorosina, Melissa Esposito, Federica Zuccalà, Miriam Vecchio, Domizia Liguori, Maria Comi, Cristoforo Comi, Giancarlo Martinelli, Vittorio Filippi, Massimo Leone, Maurizio Martinelli-Boneschi, Filippo Caputo, Domenico Sironi, Manuela Guerini, Franca Rosa D’Alfonso, Sandra Genes (Basel) Article Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease’s estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes—particularly mRNA transport—or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family. MDPI 2021-10-13 /pmc/articles/PMC8535321/ /pubmed/34681001 http://dx.doi.org/10.3390/genes12101607 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Barizzone, Nadia
Cagliani, Rachele
Basagni, Chiara
Clarelli, Ferdinando
Mendozzi, Laura
Agliardi, Cristina
Forni, Diego
Tosi, Martina
Mascia, Elisabetta
Favero, Francesco
Corà, Davide
Corrado, Lucia
Sorosina, Melissa
Esposito, Federica
Zuccalà, Miriam
Vecchio, Domizia
Liguori, Maria
Comi, Cristoforo
Comi, Giancarlo
Martinelli, Vittorio
Filippi, Massimo
Leone, Maurizio
Martinelli-Boneschi, Filippo
Caputo, Domenico
Sironi, Manuela
Guerini, Franca Rosa
D’Alfonso, Sandra
An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients
title An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients
title_full An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients
title_fullStr An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients
title_full_unstemmed An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients
title_short An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients
title_sort investigation of the role of common and rare variants in a large italian multiplex family of multiple sclerosis patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535321/
https://www.ncbi.nlm.nih.gov/pubmed/34681001
http://dx.doi.org/10.3390/genes12101607
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