Burden of rare coding variants in an Italian cohort of familial multiple sclerosis

E. Mascia, F. Clarelli, A. Zauli, C. Guaschino, M. Sorosina, N. Barizzone, C. Basagni, S. Santoro, L. Ferrè, S. Bonfiglio, D. Biancolini, M. Pozzato, F. R. Guerini, A. Protti, M. Liguori, L. Moiola, D. Vecchio, N. Bresolin, G. Comi, M. FilippiF. Esposito, S. D'Alfonso, F. Martinelli-Boneschi

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative demyelinating disease of the central nervous system. It is a complex and heterogeneous disease caused by a combination of genetic and environmental factors, and it can cluster in families. Objective: to evaluate at gene-level the aggregate contribution of predicted damaging low-frequency and rare variants to MS risk in multiplex families. Methods: We performed whole exome sequencing (WES) in 28 multiplex MS families with at least 3 MS cases (81 affected and 42 unaffected relatives) and 38 unrelated healthy controls. A gene-based burden test was then performed, focusing on two sets of candidate genes: i) literature-driven selection and ii) data-driven selection. Results: We identified 11 genes enriched with predicted damaging low-frequency and rare variants in MS compared to healthy individuals. Among them, UBR2 and DST were the two genes with the strongest enrichment (p = 5 × 10−4 and 3 × 10−4, respectively); interestingly enough the association signal in UBR2 is driven by rs62414610, which was present in 25% of analysed families. Conclusion: Despite limitations, this is one of the first studies evaluating the aggregate contribution of predicted damaging low-frequency and rare variants in MS families using WES data. A replication effort in independent cohorts is warranted to validate our findings and to evaluate the role of identified genes in MS pathogenesis.

Original languageEnglish
Article number577760
JournalJournal of Neuroimmunology
Volume362
DOIs
Publication statusPublished - Jan 15 2022

Keywords

  • Burden test
  • Candidate gene
  • Family-based study
  • Multiple sclerosis
  • Rare variants

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Neurology
  • Clinical Neurology

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