Transcript specific regulation of expression influences susceptibility to multiple sclerosis

Area of Science:

• Genetics
• Immunology
• Neuroscience

Background:

• Genome-wide association studies (GWAS) have identified over 100 genetic loci associated with multiple sclerosis (MS) risk.
• Most MS-associated loci are in non-coding regulatory regions, suggesting they influence risk by altering gene expression in immune cells.

Purpose of the Study:

• To investigate whether MS-associated variants affect gene expression by modulating allele-specific expression (ASE) of coding variants.
• To explore the mechanism by which genetic variants influence multiple sclerosis risk.

Main Methods:

• Screened genes near MS-associated variants for allele-specific expression (ASE) using coding variants in linkage disequilibrium with MS-associated single nucleotide variants (SNVs).
• Analyzed 200 coding variants in CD4+ and CD8+ T cells from MS patients and controls.
• Replicated findings for the LIME1 gene using quantitative PCR (qPCR).

Main Results:

• Identified 56 coding variants (in 43 genes) with significant ASE in T cells.
• Demonstrated that the MS-associated variant rs2256814 in the LIME1 gene alters the balance of alternate LIME1 transcripts.
• Replicated the effect of rs2256814 on LIME1 transcript balance in an independent cohort.

Conclusions:

• MS-associated SNVs likely influence disease risk by altering the balance of gene transcripts, rather than solely changing overall gene expression levels.
• These findings provide a new mechanistic understanding of how genetic risk factors contribute to multiple sclerosis.