Exome-sequencing of Turkish Families with Multiple Sclerosis: Low Frequency and Rare Variant Contributions into Susceptibility
Furkan Büyükgöl1, Berk Gürdamar1, Alper Bülbül1, Osman Ugur Sezerman1, Elif Everest2, Umut Voyvoda3, Meziyet Dilara Reda3, Özge Çetin4, Meryem Aslı Tuncer5, Bedriye Karaman6, Beril Tasdelen7, Caner Feyzi Demir8, Cavit Boz9, Cihat Uzunköprü10, Gülgün Uncu11, Haluk Gumus12, Hüsnü Efendi13, Mehmet Fatih Yetkin14, Mehmet Tecellioglu15, Meral Seferoglu16, Murat Kurtuncu17, Murat Terzi18, Muzaffer Mutluer19, Ayşe Nur Yüceyar6, Ömer Faruk Turan20, Özlem Ethemoglu21, Rana Karabudak22, Sena Destan Bunul13, Sedat Sen18, Serkan Demir7, Taskin Duman23, Tuncay Gunduz17, Ufuk Aluclu24, Yesim Beckmann25, Kaya Bilguvar26, Bade Gulec27, Melih Tutuncu27, Ugur Uygunoglu27, Sabahattin Saip27, Aksel Siva27, Eda Turanli4
1Department of Biostatistics and Bioinformatics, Graduate School of Health Sciences, Acibadem University, Istanbul, Türkiye, 2Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 3Department of Molecular Biology and Genetics, Graduate School of Natural and Applied Science, Acibadem University, Istanbul, Türkiye, 4Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences Acibadem University, Istanbul, Türkiye, 5Department of Neurology, Hacettepe University School of Medicine, Ankara, Türkiye, 6Department of Neurology, Faculty of Medicine, Ege University, İzmir, Türkiye, 7Clinic of Neurology, Sancaktepe Şehit Prof. Dr. İlhan Varank Training and Research Hospital, İstanbul, Türkiye, 8Department of Neurology, School of Medicine, Firat University, Elazığ, Türkiye, 9Department of Neurology, Karadeniz Teknik University Faculty of Medicine, Trabzon, Türkiye, 10Department of Neurology, İzmir Katip Çelebi University Faculty of Medicine, İzmir, Türkiye, 11Department of Neurology, Eskisehir City Hospital, Eskisehir, Türkiye, 12Clinic of Neurology, Selçuk University Faculty of Medicine, Konya, Türkiye, 13Department of Neurology, Kocaeli University Faculty of Medicine, Kocaeli, Türkiye, 14Department of Neurology, Erciyes University Faculty of Medicine, Kayseri, Türkiye, 15Department of Neurology, Inonu University Medical Faculty, Malatya, Türkiye, 16Department of Neurology, University Of Health Sciences Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Türkiye, 17Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkiye, 18Department of Neurology, Ondokuz Mayıs University Faculty of Medicine, Samsun, Türkiye, 19Department of Neurology, Karaman Medical Center, Karaman, Türkiye, 20Department of Neurology, Bursa Uludağ University Faculty of Medicine, Bursa, Türkiye, 21Department of Neurology, Harran University Faculty of Medicine, Şanlıurfa, Türkiye, 22Department of NeurologyYeditepe University Faculty of Medicine, Istanbul, Turkey, 23Department of Neurology, Hatay Mustafa Kemal University Faculty of Medicine, Hatay, Turkiye, 24Department of Neurology, Dicle University, School of Medicine, Diyarbakır, Türkiye, 25Department of Neurology Atatürk Training and Research Hospital Izmir, Türkiye, 26Department of Medical Genetics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye, 27Department of Neurology, İstanbul University Cerrahpaşa Faculty of Medicine, İstanbul, Türkiye
Objective:
Multiple sclerosis (MS) is characterized as an immune-mediated central nervous system disease marked by chronic inflammation, demyelination, and progressive neurodegeneration.
Background:
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 60 Turkish multiplex MS families.
Design/Methods:
Whole exome sequencing was conducted on all 215 samples including affected and unaffected members, followed by investigating the effect of well-established HLA loci for MS on the elevated MS risk observed in our families. 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. Subsequently, a gene-based burden analysis was performed on candidate genes identified through both our segregation analysis and existing literature.
Results:
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 as well as from the 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 and rs143093165 (T>G) in the ITPR1 gene which is pLI 1.00 and LOEUF 0.325, completely segregating within more than one families.
Conclusions:
This is one of the first and largest family-based MS studies from Turkey that features a unique cohort that can potentially enable 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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