{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:30:15Z","timestamp":1787027415110,"version":"build-2736575974"},"reference-count":110,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Multiple sclerosis (MS) is an immune-mediated central nervous system disease with mapped genetic risk loci but unresolved cross-layer regulatory mechanisms. We harmonised 30 primary public MS datasets spanning bulk transcriptomics (552 samples, 367 MS\/185 healthy control [HC]), DNA methylation arrays (475 samples, 244 MS\/231 HC) with sorted-cell whole-genome bisulfite sequencing (WGBS) assessment, single-cell RNA sequencing (RNA-seq; 517,533 cells from 81 donors), and cerebrospinal fluid (CSF) and brain white-matter proteomes, and UK Biobank Pharma Proteomics Project (UK Biobank-PPP) plasma proteomic statistics (407 MS\/39,979 HC) for external validation. We prioritised MS-associated genes showing inverse-concordant, cohort-level methylation\u2013expression associations and orthogonal support across layers. After harmonised reprocessing and per-stratum differential testing, a bulk-RNA \u00d7 methylation inverse-concordance filter followed by an independent proteomic and\/or donor-level single-cell anchor identified two Tier-1 candidates (IKZF1\u2019s anchor is a candidate-panel-adjusted donor-level pseudobulk association, not transcriptome-wide significance): ITGB2 and IKZF1. ITGB2 showed the strongest cross-layer support: RNA down-regulation, promoter hypermethylation and reduced plasma abundance in UK Biobank MS cases, a pattern consistent with altered leukocyte-integrin adhesion. Pathway and network analyses linked the candidates predominantly to leukocyte and lymphocyte activation and differentiation, leukocyte-integrin adhesion, and interferon and cytokine-signalling immune modules. These findings nominate MS-relevant regulatory candidates and provide a reusable multi-omics framework for hypothesis generation and validation.<\/jats:p>","DOI":"10.3390\/ijms27167275","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T13:12:56Z","timestamp":1786713176000},"page":"7275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Multi-Omics Analysis of Multiple Sclerosis Reveals Cell-Type-Specific Regulatory Landscapes and Discordant Methylation\u2013Expression Coupling"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5359-4357","authenticated-orcid":false,"given":"Alper","family":"B\u00fclb\u00fcl","sequence":"first","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, 34638 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0580-1062","authenticated-orcid":false,"given":"\u00d6zdeyi\u015f H\u00fclya","family":"Y\u0131lmaz-\u0130\u015fg\u00f6rd\u00fc","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, 34638 Istanbul, Turkey"},{"name":"Department of Molecular Biology and Genetics, Graduate School of Natural and Applied Science, Acibadem Mehmet Ali Aydinlar University, 34638 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7010-9332","authenticated-orcid":false,"given":"Meziyet Dilara","family":"Reda","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Graduate School of Natural and Applied Science, Acibadem Mehmet Ali Aydinlar University, 34638 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0789-0398","authenticated-orcid":false,"given":"Eda Tahir","family":"Turanl\u0131","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, 34638 Istanbul, Turkey"},{"name":"Department of Molecular Biology and Genetics, Graduate School of Natural and Applied Science, Acibadem Mehmet Ali Aydinlar University, 34638 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1177\/1352458520970841","article-title":"Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition","volume":"26","author":"Walton","year":"2020","journal-title":"Mult. 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