{"doi":"10.1093/g3journal/jkaf192","title":"Genome-wide discovery of multiple sclerosis genetic risk variant allelic regulatory activity","abstract":"Multiple sclerosis is an immune-mediated demyelinating disease of the central nervous system with a complex etiology involving environmental and genetic factors. 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-transformed 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.","journal":"G3 Genes Genomes Genetics","year":2025,"id":572916,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE293036"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":783818,"name":"Lois Parks","orcid":"0000-0001-5689-7492","position":1,"is_corresponding":false},{"id":1220439,"name":"Molly Shook","orcid":"0009-0001-9419-9879","position":2,"is_corresponding":false},{"id":580584,"name":"Carmy Forney","orcid":"0000-0001-6418-5794","position":3,"is_corresponding":false},{"id":229081,"name":"Xiaoting Chen","orcid":"0000-0002-3782-3962","position":4,"is_corresponding":false},{"id":3792,"name":"Lee Edsall","orcid":"0000-0002-0326-2829","position":5,"is_corresponding":false},{"id":1334668,"name":"Omer A Donmez","orcid":null,"position":6,"is_corresponding":false},{"id":250977,"name":"Sreeja Parameswaran","orcid":"0009-0002-3631-3669","position":7,"is_corresponding":false},{"id":876602,"name":"Kristen Fisher","orcid":"0000-0002-1598-8571","position":8,"is_corresponding":false},{"id":772331,"name":"Aram Zabeti","orcid":"0000-0002-0424-7460","position":9,"is_corresponding":false},{"id":1220438,"name":"Lucinda P. Lawson","orcid":"0000-0003-3939-7829","position":10,"is_corresponding":false},{"id":19923,"name":"Matthew T. Weirauch","orcid":"0000-0001-7977-9122","position":11,"is_corresponding":false},{"id":250976,"name":"Leah C. Kottyan","orcid":"0000-0003-3979-2220","position":12,"is_corresponding":false},{"id":932785,"name":"Marissa Granitto","orcid":"0000-0002-1758-9881","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:57:27.876396Z","pmid":"40838804","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}