Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Gil-Varea, Elia
• dc.contributor.author Bosch Fusté, Elena
• dc.contributor.author Navarro i Cuartiellas, Arcadi, 1969-
• dc.contributor.author Comabella López, Manuel
• dc.date.accessioned 2022-02-14T07:43:13Z
• dc.date.available 2022-02-14T07:43:13Z
• dc.date.issued 2020
• dc.description.abstract 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.
• dc.description.sponsorship Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarollo Regional (FEDER). Grant Number: BFU2016-77961-P
• dc.format.mimetype application/pdf
• dc.identifier.citation 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
• dc.identifier.doi http://dx.doi.org/10.1002/humu.24016
• dc.identifier.issn 1059-7794
• dc.identifier.uri http://hdl.handle.net/10230/52480
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.ispartof Hum Mutat. 2020;41(7):1308-20
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-77961-P
• dc.rights This 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.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword RGS1
• dc.subject.keyword Interferon-β
• dc.subject.keyword Multiple sclerosis
• dc.subject.keyword Rare variants
• dc.subject.keyword Single nucleotide polymorphisms
• dc.subject.keyword Targeted DNA sequencing
• dc.title Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion