Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes

Although genome-wide association studies have identified a number of common variants associated with multiple sclerosis (MS) susceptibility, little is known about the relevance of rare variants. Here, we aimed to explore the role of rare variants in 14 MS risk genes (FCRL1, RGS1, TIMMDC1, HHEX, CXCR...

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Autores: Gil-Varea, Elia, Bosch Fusté, Elena, Navarro i Cuartiellas, Arcadi, 1969-, Comabella López, Manuel
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2020
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/52480
Acceso en línea:http://hdl.handle.net/10230/52480
http://dx.doi.org/10.1002/humu.24016
Access Level:acceso abierto
Palabra clave:RGS1
Interferon-β
Multiple sclerosis
Rare variants
Single nucleotide polymorphisms
Targeted DNA sequencing
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spelling Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genesGil-Varea, EliaBosch Fusté, ElenaNavarro i Cuartiellas, Arcadi, 1969-Comabella López, ManuelRGS1Interferon-βMultiple sclerosisRare variantsSingle nucleotide polymorphismsTargeted DNA sequencingAlthough genome-wide association studies have identified a number of common variants associated with multiple sclerosis (MS) susceptibility, little is known about the relevance of rare variants. Here, we aimed to explore the role of rare variants in 14 MS risk genes (FCRL1, RGS1, TIMMDC1, HHEX, CXCR5, LTBR, TSFM, GALC, TRAF3, STAT3, TNFSF14, IFI30, CD40, and CYP24A1) by targeted resequencing in an Iberian population of 524 MS cases and 546 healthy controls. Four rare variants-enriched regions within CYP24A1, FCRL1, RGS1, and TRAF3 were identified as significantly associated with MS. Functional studies revealed significantly decreased regulator of G protein signaling 1 (RGS1) gene expression levels in peripheral blood mononuclear cells from MS patients with RGS1 rare variants compared to noncarriers, whereas no significant differences in gene expression were observed for CYP24A1, FCRL1, and TRAF3 between rare variants carriers and noncarriers. Immunophenotyping showed significant decrease in RGS1 expression in peripheral blood B lymphocytes from MS patients with RGS1 rare variants relative to noncarriers. Lastly, peripheral blood mononuclear cell from MS patients carrying RGS1 rare variants showed significantly lower induction of RGS1 gene expression by interferon-β compared to MS patients lacking RGS1 variants. The presence of rare variants in RGS1 reinforce the ideas of high genetic heterogeneity and a role of rare variants in MS pathogenesis.Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarollo Regional (FEDER). Grant Number: BFU2016-77961-PWiley202220222020info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/52480http://dx.doi.org/10.1002/humu.24016reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésHum Mutat. 2020;41(7):1308-20info:eu-repo/grantAgreement/ES/1PE/BFU2016-77961-PThis is the peer reviewed version of the following article: Gil-Varea E, Spataro N, Villar LM, Tejeda-Velarde A, Midaglia L, Matesanz F et al. Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes. Hum Mutat. 2020;41(7):1308-20. DOI: 10.1002/humu.24016, which has been published in final form at http://dx.doi.org/10.1002/humu.24016. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/524802026-06-12T07:21:37Z
dc.title.none.fl_str_mv Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes
title Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes
spellingShingle Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes
Gil-Varea, Elia
RGS1
Interferon-β
Multiple sclerosis
Rare variants
Single nucleotide polymorphisms
Targeted DNA sequencing
title_short Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes
title_full Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes
title_fullStr Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes
title_full_unstemmed Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes
title_sort Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes
dc.creator.none.fl_str_mv Gil-Varea, Elia
Bosch Fusté, Elena
Navarro i Cuartiellas, Arcadi, 1969-
Comabella López, Manuel
author Gil-Varea, Elia
author_facet Gil-Varea, Elia
Bosch Fusté, Elena
Navarro i Cuartiellas, Arcadi, 1969-
Comabella López, Manuel
author_role author
author2 Bosch Fusté, Elena
Navarro i Cuartiellas, Arcadi, 1969-
Comabella López, Manuel
author2_role author
author
author
dc.subject.none.fl_str_mv RGS1
Interferon-β
Multiple sclerosis
Rare variants
Single nucleotide polymorphisms
Targeted DNA sequencing
topic RGS1
Interferon-β
Multiple sclerosis
Rare variants
Single nucleotide polymorphisms
Targeted DNA sequencing
description Although genome-wide association studies have identified a number of common variants associated with multiple sclerosis (MS) susceptibility, little is known about the relevance of rare variants. Here, we aimed to explore the role of rare variants in 14 MS risk genes (FCRL1, RGS1, TIMMDC1, HHEX, CXCR5, LTBR, TSFM, GALC, TRAF3, STAT3, TNFSF14, IFI30, CD40, and CYP24A1) by targeted resequencing in an Iberian population of 524 MS cases and 546 healthy controls. Four rare variants-enriched regions within CYP24A1, FCRL1, RGS1, and TRAF3 were identified as significantly associated with MS. Functional studies revealed significantly decreased regulator of G protein signaling 1 (RGS1) gene expression levels in peripheral blood mononuclear cells from MS patients with RGS1 rare variants compared to noncarriers, whereas no significant differences in gene expression were observed for CYP24A1, FCRL1, and TRAF3 between rare variants carriers and noncarriers. Immunophenotyping showed significant decrease in RGS1 expression in peripheral blood B lymphocytes from MS patients with RGS1 rare variants relative to noncarriers. Lastly, peripheral blood mononuclear cell from MS patients carrying RGS1 rare variants showed significantly lower induction of RGS1 gene expression by interferon-β compared to MS patients lacking RGS1 variants. The presence of rare variants in RGS1 reinforce the ideas of high genetic heterogeneity and a role of rare variants in MS pathogenesis.
publishDate 2020
dc.date.none.fl_str_mv 2020
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/52480
http://dx.doi.org/10.1002/humu.24016
url http://hdl.handle.net/10230/52480
http://dx.doi.org/10.1002/humu.24016
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Hum Mutat. 2020;41(7):1308-20
info:eu-repo/grantAgreement/ES/1PE/BFU2016-77961-P
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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