@article{63bb7ffc5a61489dbc228af105190b31,
title = "Burden of rare coding variants in an Italian cohort of familial multiple sclerosis",
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.",
keywords = "Burden test, Candidate gene, Family-based study, Multiple sclerosis, Rare variants",
author = "E. Mascia and F. Clarelli and A. Zauli and C. Guaschino and M. Sorosina and N. Barizzone and C. Basagni and S. Santoro and L. Ferr{\`e} and S. Bonfiglio and D. Biancolini and M. Pozzato and Guerini, {F. R.} and A. Protti and M. Liguori and L. Moiola and D. Vecchio and N. Bresolin and G. Comi and M. Filippi and F. Esposito and S. D'Alfonso and F. Martinelli-Boneschi",
note = "Funding Information: This study was funded by the Ricerca Finalizzata of the Italian Ministry of Health ( RF-2011-02350347 ); FISM ( 2011/R/14 2015/R/10 , 2019/R-Multi/033 , grants). Funding Information: CG received financial support for attending meetings from Sanofi Genzyme, Merck Serono, Biogen and Novartis. Funding Information: This study was funded by the Ricerca Finalizzata of the Italian Ministry of Health (RF-2011-02350347); FISM (2011/R/14 2015/R/10, 2019/R-Multi/033, grants).MF is Editor-in-Chief of the Journal of Neurology; serves on the scientific advisory board for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, Alzheimer's Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA).FMB has received compensation for consulting services and/or speaking activities from Teva Pharmaceutical Industries, Sanofi Genzyme, Merck-Serono, Biogen Idec, Roche, Medday, Excemed, and received research support from Merck, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla and Fondazione Cariplo. Publisher Copyright: {\textcopyright} 2021 Elsevier B.V.",
year = "2021",
month = nov,
day = "5",
doi = "10.1016/j.jneuroim.2021.577760",
language = "English",
volume = "362",
journal = "Journal of Neuroimmunology",
issn = "0165-5728",
publisher = "Elsevier Science B.V.",
}