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Numerous genetic risk loci for multiple sclerosis have been nominated through genome-wide association studies, with most associated variants residing in noncoding regions. However, further work is needed to understand how genetic variation contributes to disease-related alterations to gene expression. Here, we use Massively Parallel Reporter Assays to identify genetic risk variants with genotype-dependent enhancing or silencing activity within a set of 14,275 variants distributed among multiple sclerosis risk loci that have reached genome-wide or suggestive significance. We applied our Massively Parallel Reporter Assay library to Epstein-Barr-virus\u2013transformed B cell lines derived from two patients with multiple sclerosis, as well as the ENCODE Tier 1 cell line GM12878. In total, our approach discovered 150 allelic enhancing variants and 286 allelic silencing variants, collectively representing 83 independent multiple sclerosis risk loci. Our systematic, genome-scale approach implicates potentially causal genotype-dependent gene regulatory mechanisms for over a third of the known multiple sclerosis risk loci, providing a unique resource for the discovery of the genetic mechanisms underlying this chronic inflammatory disease.<\/jats:p>","DOI":"10.1093\/g3journal\/jkaf192","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T13:39:15Z","timestamp":1755783555000},"source":"Crossref","is-referenced-by-count":1,"title":["Genome-wide discovery of multiple sclerosis genetic risk variant allelic regulatory activity"],"prefix":"10.1093","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1758-9881","authenticated-orcid":false,"given":"Marissa","family":"Granitto","sequence":"first","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Development, Stem Cells & Regenerative Medicine Graduate Program, University of Cincinnati , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lois","family":"Parks","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Immunology Graduate Program, University of Cincinnati , Cincinnati, OH 45229 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly S","family":"Shook","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmy","family":"Forney","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee E","family":"Edsall","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omer A","family":"Donmez","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sreeja","family":"Parameswaran","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen S","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neurology and Developmental Neuroscience, Baylor College of Medicine , Houston, TX 77030 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0424-7460","authenticated-orcid":false,"given":"Aram","family":"Zabeti","sequence":"additional","affiliation":[{"name":"Wadell Center for Multiple Sclerosis, College of Medicine, University of Cincinnati , Cincinnati, OH 45220 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3939-7829","authenticated-orcid":false,"given":"Lucinda P","family":"Lawson","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7977-9122","authenticated-orcid":false,"given":"Matthew T","family":"Weirauch","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Developmental Biology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Department of Pediatrics, University of Cincinnati, College of Medicine , Cincinnati, OH 45229 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3979-2220","authenticated-orcid":false,"given":"Leah C","family":"Kottyan","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 45229 ,","place":["United States"]},{"name":"Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center , Cincinnati, OH 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