Exome sequencing reveals low-frequency and rare variant contributions to multiple sclerosis susceptibility in Turkish families

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dc.contributor.authorBuyukgol, Furkan
dc.contributor.authorGurdamar, Berk
dc.contributor.authorAluclu, Mehmet Ufuk
dc.contributor.authorBeckmann, Yesim
dc.contributor.authorBilguvar, Kaya
dc.contributor.authorBoz, Cavit
dc.contributor.authorBulbul, Alper
dc.date.accessioned2026-04-04T13:34:41Z
dc.date.available2026-04-04T13:34:41Z
dc.date.issued2025
dc.departmentİnönü Üniversitesi
dc.description.abstractMultiple sclerosis (MS) is characterized as an immune-mediated central nervous system disease marked by chronic inflammation, demyelination, and progressive neurodegeneration. In this study, we evaluated the contribution of low-frequency and rare genetic variants to MS susceptibility within one of the largest family-based MS cohorts to date, comprising 215 individuals from 59 Turkish multiplex MS families. Whole exome sequencing was conducted on all samples including affected and unaffected members, followed by investigation of the effect of well-established human leukocyte antigen loci for MS on the elevated MS risk observed in our families. Subsequently, a gene-based burden analysis was performed on candidate genes identified through both our segregation analysis and existing literature. To prioritize the genes and pathways that are potentially associated with MS, a segregation-based analysis of the variants was conducted and complemented by gene-based pathway enrichment analysis. Our results highlighted the significance of the extracellular matrix in MS pathogenesis, as we identified laminin-related genes including LAMA5 and LAMB1 from both the segregation analysis and gene-based burden test. Hemidesmosome assembly emerged as a key pathway in our analysis, primarily driven by the identification of DST and PLEC as significant genes in the gene-based segregation analysis. Finally, we identified two rare coding variants passing our allele frequency and deleteriousness score-based filters, rs41266745 (C> T) in the CD109 gene with CADD phred score 24 and rs143093165 (T> G) in the ITPR1 gene with CADD phred score 22 and LOEUF 0.325, segregating within more than one family. Overall, this is one of the first and largest family-based MS studies from Turkey that features a unique cohort from an admixed population that enabled the detection of novel low-frequency and rare variants associated with MS. The findings from this study offer valuable insights that could guide future research aimed at further exploring and understanding the factors contributing to MS risk.
dc.description.sponsorshipIstanbul University-Cerrahpasa Scientific Research Projects [26360]; Istanbul Technical University Scientific Research Projects [41964]; Turkish MS Society Award Project [41]; Turkish Scientific and Technological Research Council of Turkey (TUBITAK) [ARDEB 1002, 220S889]; ARDEB 1001 [123Z072]; Laboratory Core of the Collaborative Health Initiative Research Program
dc.description.sponsorshipResearch grants for this study have been received from Istanbul University-Cerrahpasa Scientific Research Projects (No. 26360), Istanbul Technical University Scientific Research Projects (No. 41964), Turkish MS Society Award Project (No. 41), Turkish Scientific and Technological Research Council of Turkey (TUBITAK) ARDEB 1002 (No. 220S889), and ARDEB 1001 (No. 123Z072). We thank Clifon L. Dalgard and Uniformed Services University, Laboratory Core of the Collaborative Health Initiative Research Program, as well as Yale Center for Genome Analysis, for sequencing services. We would also like to thank all the MS family members for their contribution.
dc.identifier.doi10.1038/s41598-025-94691-x
dc.identifier.issn2045-2322
dc.identifier.issue1
dc.identifier.orcid0000-0002-0789-0398
dc.identifier.orcid0000-0003-3858-0306
dc.identifier.orcid0009-0009-4173-3327
dc.identifier.orcid0009-0006-5888-0735
dc.identifier.orcid0000-0003-4241-0908
dc.identifier.orcid0000-0001-5876-8643
dc.identifier.orcid0000-0002-8340-6641
dc.identifier.pmid40188234
dc.identifier.scopus2-s2.0-105003089394
dc.identifier.scopusqualityN/A
dc.identifier.urihttps://doi.org/10.1038/s41598-025-94691-x
dc.identifier.urihttps://hdl.handle.net/11616/109323
dc.identifier.volume15
dc.identifier.wosWOS:001460360100012
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherNature Portfolio
dc.relation.ispartofScientific Reports
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WOS_20250329
dc.subjectGenetics
dc.subjectFamilial multiple sclerosis
dc.subjectBlood-brain barrier
dc.subjectWhole exome sequencing
dc.titleExome sequencing reveals low-frequency and rare variant contributions to multiple sclerosis susceptibility in Turkish families
dc.typeArticle

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