Scientific Reports (Apr 2025)
Exome sequencing reveals low-frequency and rare variant contributions to multiple sclerosis susceptibility in Turkish families
- Furkan Büyükgöl,
- Berk Gürdamar,
- Mehmet Ufuk Aluçlu,
- Yeşim Beckmann,
- Kaya Bilguvar,
- Cavit Boz,
- Alper Bülbül,
- Sena Destan Bünül,
- Özge Çetin,
- Caner Feyzi Demir,
- Serkan Demir,
- Taşkın Duman,
- Hüsnü Efendi,
- Özgül Ekmekçi,
- Utku Ertetik,
- Özlem Ethemoğlu,
- Elif Everest,
- Haluk Gümüş,
- Tuncay Gündüz,
- Rana Karabudak,
- Bedriye Karaman,
- Murat Kürtüncü,
- Muzaffer Mutluer,
- Meziyet Dilara Reda,
- Sabahattin Saip,
- Meral Seferoğlu,
- Elif Sever,
- Osman Ugur Sezerman,
- Sedat Şen,
- Beril Taşdelen,
- Mehmet Tecellioğlu,
- Murat Terzi,
- Aslı Tuncer,
- Ömer Faruk Turan,
- Melih Tütüncü,
- Gülgün Uncu,
- Uğur Uygunoğlu,
- Cihat Uzunköprü,
- Umut Voyvoda,
- Mehmet Fatih Yetkin,
- Nur Yüceyar,
- Aksel Siva,
- Eda Tahir Turanlı
Affiliations
- Furkan Büyükgöl
- Department of Biostatistics and Bioinformatics, Institute of Health Sciences, Acibadem Mehmet Ali Aydınlar University
- Berk Gürdamar
- Department of Biostatistics and Bioinformatics, Institute of Health Sciences, Acibadem Mehmet Ali Aydınlar University
- Mehmet Ufuk Aluçlu
- Department of Neurology, School of Medicine, Dicle University
- Yeşim Beckmann
- Department of Neurology, Izmir Katip Çelebi University
- Kaya Bilguvar
- Department of Neurosurgery and Genetics, Yale Program on Neurogenetics and Brain Tumor Research Program, Yale Center of Genome Analysis, Yale School of Medicine
- Cavit Boz
- Department of Neurology, Karadeniz Technical University Medical School
- Alper Bülbül
- Department of Biostatistics and Bioinformatics, Institute of Health Sciences, Acibadem Mehmet Ali Aydınlar University
- Sena Destan Bünül
- Department of Neurology, Faculty of Medicine, Kocaeli University
- Özge Çetin
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydınlar University
- Caner Feyzi Demir
- Department of Neurology, School of Medicine, Firat University
- Serkan Demir
- Clinic of Neurology, Sancaktepe Şehit Prof. Dr. Ilhan Varank Training and Research Hospital
- Taşkın Duman
- Department of Neurology, Faculty of Medicine, Hatay Mustafa Kemal University
- Hüsnü Efendi
- Department of Neurology, Faculty of Medicine, Kocaeli University
- Özgül Ekmekçi
- Department of Neurology, Ege University
- Utku Ertetik
- Department of Medical Biotechnology, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydınlar University
- Özlem Ethemoğlu
- Department of Neurology, Faculty of Medicine, Harran University
- Elif Everest
- Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke National Institutes of Health
- Haluk Gümüş
- Clinic of Neurology, Faculty of Medicine, Selçuk University
- Tuncay Gündüz
- Department of Neurology, Istanbul Faculty of Medicine, Istanbul University
- Rana Karabudak
- Department of Neurology, Yeditepe University Hospitals
- Bedriye Karaman
- Department of Neurology, Ege University
- Murat Kürtüncü
- Department of Neurology, Istanbul Faculty of Medicine, Istanbul University
- Muzaffer Mutluer
- Department of Neurology, Karaman Medical Center
- Meziyet Dilara Reda
- Department of Molecular Biology and Genetics, Institute of Natural and Applied Science, Acibadem Mehmet Ali Aydınlar University
- Sabahattin Saip
- Department of Neurology, Faculty of Medicine, Istanbul University Cerrahpaşa
- Meral Seferoğlu
- Department of Neurology, University Of Health Sciences Bursa Yuksek Ihtisas Training and Research Hospital
- Elif Sever
- Department of Biostatistics and Bioinformatics, Institute of Health Sciences, Acibadem Mehmet Ali Aydınlar University
- Osman Ugur Sezerman
- Department of Biostatistics and Bioinformatics, Institute of Health Sciences, Acibadem Mehmet Ali Aydınlar University
- Sedat Şen
- Department of Neurology, Faculty of Medicine, Ondokuz Mayıs University
- Beril Taşdelen
- Clinic of Neurology, Sancaktepe Şehit Prof. Dr. Ilhan Varank Training and Research Hospital
- Mehmet Tecellioğlu
- Department of Neurology, Medical Faculty, Inonu University
- Murat Terzi
- Department of Neurology, Faculty of Medicine, Ondokuz Mayıs University
- Aslı Tuncer
- Department of Neurology, Faculty of Medicine, Hacettepe University
- Ömer Faruk Turan
- Department of Neurology, Faculty of Medicine, Bursa Uludaǧ University
- Melih Tütüncü
- Department of Neurology, Faculty of Medicine, Istanbul University Cerrahpaşa
- Gülgün Uncu
- Eskisehir City Health Application and Research Center, Department of Neurology, University of Health Sciences
- Uğur Uygunoğlu
- Department of Neurology, Faculty of Medicine, Istanbul University Cerrahpaşa
- Cihat Uzunköprü
- Department of Neurology, Izmir Katip Çelebi University
- Umut Voyvoda
- Department of Molecular Biology and Genetics, Institute of Natural and Applied Science, Acibadem Mehmet Ali Aydınlar University
- Mehmet Fatih Yetkin
- Department of Neurology, Faculty of Medicine, Erciyes University
- Nur Yüceyar
- Department of Neurology, Ege University
- Aksel Siva
- Department of Neurology, Faculty of Medicine, Istanbul University Cerrahpaşa
- Eda Tahir Turanlı
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydınlar University
- DOI
- https://doi.org/10.1038/s41598-025-94691-x
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 14
Abstract
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.
Keywords
