Genomic regions associated with multiple sclerosis are active in B cells

Area of Science:

• Genomics
• Immunology
• Neuroscience

Background:

• Over 50 genomic regions are linked to multiple sclerosis (MS) risk, but their molecular mechanisms and cell-type specificity are largely unknown.
• Understanding the cell types where MS-associated variants function is crucial for elucidating disease pathogenesis, especially for regions without known genes.

Purpose of the Study:

• To investigate whether MS-associated genomic regions are functionally active in B cells, hypothesizing a co-localization due to the known role of B cells in MS.
• To compare the enrichment of MS risk variants in B cells versus control cell types (hepatocytes, fibroblasts, keratinocytes).

Main Methods:

• Utilized publicly available data on MS-associated regions and single nucleotide polymorphisms (SNPs).
• Analyzed chromatin profiling data from B cells and three control cell types.
• Employed the Genomic Hyperbrowser to test for overlaps between MS-associated regions/SNPs and functional genomic elements.

Main Results:

• MS-associated regions showed significant enrichment in active regulatory elements (enhancers, promoters) and transcribed regions in B cells (p<0.00005).
• This enrichment was significantly higher in B cells compared to control cell types.
• MS-associated SNPs were also found at higher-than-expected frequencies in active promoter and enhancer regions (p<0.00005).

Conclusions:

• The findings strongly support a significant role for B cells in multiple sclerosis pathogenesis.
• MS risk variants likely exert their effects through gene regulation within B cells.
• Previous studies focusing on T cells may have overlooked critical B cell-specific contributions to MS risk.