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

Multiple 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.

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Publication Details

Journal
Scientific Reports
Published
2025-04-05
DOI
https://doi.org/10.1038/s41598-025-94691-x
Citations
2
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
1.61
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article

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

Aslı Tuncer, Mehmet Ufuk Aluçlu, Melih Tütüncü, Murat Terzi et al.
2 citations
Scientific Reports
RNA Research and Splicing
1.61
article

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

Aslı Tuncer, Mehmet Ufuk Aluçlu, Melih Tütüncü, Murat Terzi, Özge Çetin, Alper Bülbül, Utku Ertetik, Özlem Ethemoğlu, Manon Réda, Ömer Faruk Turan, Elif Sever, Sabahattin Saip, Nur Yüceyar, Mehmet Tecellioğlu, Eda Tahir Turanlı, Osman Uğur Sezerman, Berk Gürdamar, Özgül Ekmekçi, Tuncay Gündüz, Serkan Demir, Cavit Boz, Elif Everest, Aksel Sıva, Kaya Bilgüvar, Haluk Gümüş, Hüsnü Efendi, Gülgün Uncu, Bedriye Karaman, Uğur Uygunoğlu, Cihat Uzunköprü, Sena Destan Bünül, Sedat Şen, Rana Karabudak, Yeşim Beckmann, Mehmet Fatih Yetkin, Taşkın Duman, Meral Seferoğlu, Caner Feyzi Demir, Umut Voyvoda, Murat Kürtüncü, Beril Taşdelen, Furkan Büyükgöl, Muzaffer Mutluer
article en
2 citations

Abstract

Multiple 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.

Scientific ReportsVol. 15(1)
Dicle University (TR), Karadeniz Technical University (TR), Ondokuz Mayıs University (TR), Izmir Kâtip Çelebi University (TR), Ege University (TR), Istanbul University-Cerrahpaşa (TR), Kent Hastanesi (TR), Acıbadem Adana Hospital (TR), Mustafa Kemal University (TR), Kocaeli Üniversitesi (TR), Hacettepe University (TR), Istanbul University (TR), Erciyes University (TR)
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RNA Research and Splicing
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