GWAS highlights the neuronal contribution to multiple sclerosis susceptibility

Area of Science:

• Neuroimmunology
• Genetics
• Neurodegenerative Diseases

Background:

• Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative disease impacting the central nervous system.
• Previous genetic studies suggested MS risk loci primarily affect immune cells and microglia.

Purpose of the Study:

• To conduct a large-scale, multi-ancestry genome-wide association study (GWAS) to identify novel genetic susceptibility loci for MS.
• To investigate the cell types and genes influenced by MS risk variants using integrated single-cell data.

Main Methods:

• Performed a multi-ancestry GWAS including 20,831 MS cases and 729,220 controls.
• Identified 236 MS susceptibility variants outside the Major Histocompatibility Complex (MHC).
• Integrated single-cell RNA sequencing data from blood and brain tissue to identify affected genes and cell types.

Main Results:

• Identified 236 MS susceptibility variants, including four novel loci.
• Developed a polygenic score for MS, effective across European, African-American, and Latino ancestries.
• Found 76 genes affected by MS risk variants, with T cells showing strong enrichment and inhibitory neurons emerging as a key cell type.

Conclusions:

• Genetic susceptibility to MS involves a broader range of cell types than previously recognized.
• Highlights the significant role of neuronal and glial dysfunction in MS pathogenesis.
• Provides a more comprehensive genetic architecture of MS across diverse ancestries.