Identification of differential DNA methylation associated with multiple sclerosis: A family-based study

• Published in: Journal of neuroimmunology Vol. 356; p. 577600
• Main Authors: Garcia-Manteiga, J.M., Clarelli, F., Bonfiglio, S., Mascia, E., Giannese, F., Barbiera, G., Guaschino, C., Sorosina, M., Santoro, S., Protti, A., Martinelli, V., Cittaro, D., Lazarevic, D., Stupka, E., Filippi, M., Esposito, F., Martinelli-Boneschi, F.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.07.2021
• Subjects: Autoimmune diseases; Epigenetics; Familial multiple sclerosis; Genomics; Methylation; Multiple sclerosis; Epigenetics; Multiple sclerosis; Methylation; Autoimmune diseases; Genomics; Familial multiple sclerosis
• ISSN: 0165-5728; 1872-8421
• DOI: 10.1016/j.jneuroim.2021.577600

Multiple Sclerosis (MS) is caused by a still unknown interplay between genetic and environmental factors. Epigenetics, including DNA methylation, represents a model for environmental factors to influence MS risk. Twenty-six affected and 26 unaffected relatives from 8 MS multiplex families were analysed in a multicentric Italian study using MeDIP-Seq, followed by technical validation and biological replication in two additional families of differentially methylated regions (DMRs) using SeqCap Epi Choice Enrichment kit (Roche®). Associations from MeDIP-Seq across families were combined with aggregation statistics, yielding 162 DMRs at FDR ≤ 0.1. Technical validation and biological replication led to 2 hypo-methylated regions, which point to NTM and BAI3 genes, and to 2 hyper-methylated regions in PIK3R1 and CAPN13. These 4 novel regions contain genes of potential interest that need to be tested in larger cohorts of patients. [Display omitted] •The 233 genetic loci associated with MS explain less than 40% of disease heritability, leaving a role to epigenetics in disease risk•We compared whole-genome methylation profiles in whole blood of affected and unaffected relatives of 8 multiplex MS families•We used MeDIP-seq and technical and biological replication in 2 additional families using a custom panel•Due to the heterogeneity of results in families, we adopted a method which leveraged consistency of signal across families•Filtering criteria lead to 2 hypo- and 2 hyper-methylated DMRs which relate to NTM, BAI3, PIK3R1 and CAPN13 genes•Replication of these signals is needed in additional cohort of MS patients