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Publications

Journal Article Ahead of print

PubMed: 42706309 DOI: 10.1038/s41588-026-02731-7

Genome-wide association analyses highlight the neuronal contribution to multiple sclerosis susceptibility.

Nat Genet

Authors: Lu Zeng, Atlas Khan, Kathryn C Fitzgerald, Tsering Lama, Jessy Chen, Ruixi Li, Ellen A Tsai, Ketian Yu, Tanuja Chitnis, Howard L Weiner, Quentin Le Grand, Stéphanie Debette, Gao Wang, Masashi Fujita, Peter A Calabresi, Frauke Zipp, Mariko Taga, Krzysztof Kiryluk, Philip L De Jager

Affiliations

  • Center for Translational and Computational Neuroimmunology & Columbia Multiple Sclerosis Center, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
  • Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
  • Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • The Gertrude H. Sergievsky Center and the Department of Neurology, Columbia University, New York, NY, USA.
  • Biogen, Biomarkers and Systems Biology, Cambridge, MA, USA.
  • Ann Romney Center for Neurologic Diseases and Brigham Multiple Sclerosis Center, Department of Neurology, Brigham & Women's Hospital, Mass General Brigham, Boston, MA, USA.
  • Bordeaux Population Health Research Center, INSERM, UMR1219, University of Bordeaux, Bordeaux, France.
  • Bordeaux University Hospital, Department of Neurology, Institute for Neurodegenerative Diseases, Bordeaux, France.
  • Department of Neurology, Research Center for Immunotherapy (FZI) and Focus Program Translational Neuroscience (FTN), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • Center for Translational and Computational Neuroimmunology & Columbia Multiple Sclerosis Center, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Previous genetic studies have identified susceptibility loci that primarily impact immune cells and microglia. Here we performed a multi-ancestry genome-wide association study of 20,831 MS cases and 729,220 controls and identified 236 susceptibility variants outside of the major histocompatibility complex, including four novel genomic loci. We also derived a polygenic score for MS; while optimized for European ancestry, it is informative for African American and Latino individuals. Integrating single-cell data from blood and brain tissue, we identified 76 candidate causal genes. Inhibitory neurons emerged as a key target cell type for MS-associated variants, with seven loci, including STAT3, displaying altered expression only in these cells. The STAT3 variant is also associated with cognition and white matter integrity in individuals with no MS and greater sNfL levels in individuals with MS, suggesting that MS susceptibility may reflect reduced central nervous system resilience to inflammatory challenges.

MeSH

Cells, Sclerosis, Multiple Sclerosis, Major Histocompatibility Complex, Genome, Genetics, Medical