GWAS highlights the neuronal contribution to multiple sclerosis susceptibility

Area of Science:

• Neuroimmunology
• Genetics
• Neuroscience

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 multi-ancestry genome-wide association study (GWAS) to identify novel MS susceptibility variants.
• To investigate the cell types and genes influenced by MS risk variants using single-cell data.
• To assess the utility of a polygenic score for MS across diverse ancestries.

Main Methods:

• Performed a large-scale, multi-ancestry GWAS including 20,831 MS cases and 729,220 controls.
• Integrated single-cell RNA sequencing data from blood and brain tissue.
• Derived and evaluated a polygenic risk score for MS.

Main Results:

• Identified 236 MS susceptibility variants outside the Major Histocompatibility Complex (MHC), including four novel loci.
• Found 76 genes affected by MS risk variants, with T cells showing strong enrichment.
• Discovered that inhibitory neurons are a key cell type, with specific gene expression changes (IL7, STAT3) observed only in this population.
• Demonstrated that an MS polygenic score optimized for European ancestry is also informative for African-American and Latino participants.

Conclusions:

• Genetic susceptibility to MS involves a broader range of cell types than previously recognized, notably including inhibitory neurons.
• Neuronal and glial dysfunction play a significant role in MS pathogenesis.
• The identified genetic variants and affected genes provide new targets for understanding and potentially treating MS.