X-chromosome methylation patterns in females with multiple sclerosis
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Multiple sclerosis (MS) is approximately three times more common in females than in males, but sex-linked epigenetic mechanisms remain incompletely understood. We tested whether X-chromosome DNA methylation differs in females with MS and whether associated sites preferentially map to genes normally subject to X-chromosome inactivation (XCI). An X-chromosome-focused epigenome-wide association study was performed in whole blood from three datasets comprising 496 females with MS and 509 female controls, with independent evaluation in isolated CD4+ T cells (80 cases, 76 controls). At FDR < 0.01, 3 182 X-chromosome CpGs were hypomethylated in MS (mean Δβ = −0.035). Hypomethylated CpGs were strongly enriched in non-escape genes normally subject to XCI relative to escape genes (OR 6.77; p = 1.55×10) and mapped to immune and chromatin-related processes. Exploratory cis-mQTL analysis identified strong local genetic effects at a small subset of loci, including WAS, IRAK1 and TLR7. In CD4+ T cells, 2 080 of the 3 182 whole-blood hypomethylated CpGs (65.4%) were also significantly hypomethylated. These findings identify a reproducible X-chromosome hypomethylation signature in female MS and support direct investigation of inactive-X regulation, XCI escape and X-linked immune gene dosage.
Source: medRxiv
Institutions: Hunter Medical Research Institute, University of Newcastle Australia, John Hunter Hospital, Hunter New England Local Health District, The University of Melbourne, Florey Institute of Neuroscience and Mental Health, University of Tasmania, Menzies Institute for Medical Research, Griffith University, Monash University, Karolinska University Hospital, Karolinska Institutet
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7221749979