Genome-Wide Discovery of Multiple Sclerosis Genetic Risk Variant Allelic Regulatory Activity

Authors

• Marissa Granitto
• Lois Parks
• Molly S Shook
• Carmy Forney
• Xiaoting Chen
• Lee E Edsall
• Omer A Donmez
• Sreeja Parameswaran
• Kristen S Fisher
• Aram Zabeti
• Lucinda P Lawson
• Matthew T Weirauch
• Leah C Kottyan

Language

English

Publication Date

11-12-2025

Journal

G3: Genes, Genomes, Genetics

DOI

10.1093/g3journal/jkaf192

PMID

40838804

PMCID

PMC12608076

PubMedCentral® Posted Date

8-21-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Multiple Sclerosis, Genome-Wide Association Study, Genetic Predisposition to Disease, Alleles, Polymorphism, Single Nucleotide, Genetic Variation, Cell Line, Genotype

Published Open-Access

yes

Recommended Citation

Granitto, Marissa; Parks, Lois; Shook, Molly S; et al., "Genome-Wide Discovery of Multiple Sclerosis Genetic Risk Variant Allelic Regulatory Activity" (2025). Faculty, Staff and Students Publications. 7694.
https://digitalcommons.library.tmc.edu/baylor_docs/7694