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09:41
Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
12.0K
Interpreting Non-coding Genetic Variation in Multiple Sclerosis Genome-Wide Associated Regions.
Elvezia Maria Paraboschi1, Giulia Cardamone1, Giulia Soldà1,2
1Department of Biomedical Sciences, Humanitas University, Milan, Italy.
Frontiers in Genetics
|January 9, 2019
Summary
This study reveals that circular RNAs (circRNAs) are enriched in regions linked to multiple sclerosis (MS) susceptibility. These non-coding RNAs may play a role in the complex genetic basis of MS.
Area of Science:
- Genetics
- Neuroimmunology
- Molecular Biology
Background:
- Multiple sclerosis (MS) is a leading cause of neurological disability in young adults, with a significant portion of its heritability remaining unexplained.
- Current genetic studies predominantly focus on protein-coding genes, overlooking the regulatory roles of non-coding RNAs (ncRNAs) and functional elements like super-enhancers.
- ncRNAs and super-enhancers are increasingly recognized as critical regulators in disease pathogenesis.
Purpose of the Study:
- To investigate the enrichment of non-coding elements, particularly circular RNAs (circRNAs), within genome-wide association study (GWAS) loci associated with MS.
- To explore the potential involvement of these non-coding elements in MS susceptibility.
Main Methods:
- Reconstruction of linkage disequilibrium (LD) structure in an Italian population using 727,478 single-nucleotide polymorphisms (SNPs) from 1,668 healthy individuals.
- Intersection of LD blocks with MS-associated SNPs from published GWAS.
- Bootstrapping analysis to assess the enrichment of non-coding elements, specifically circRNAs, within MS-associated LD blocks.
Main Results:
- A significant enrichment of circRNAs was observed in 73 LD blocks containing MS-associated SNPs, with 482 identified circRNAs compared to a mean of 194 ± 65 in random sets.
- Experimental validation confirmed that the expression of a circRNA (hsa_circ_0043813) from the STAT3 gene locus is modulated by MS-associated SNP genotypes.
- RNA sequencing identified 18 circRNAs, including two novel ones, derived from MS-associated genes in relevant cell lines (SH-SY5Y and Jurkat).
Conclusions:
- This study provides the first evidence that MS GWAS top hits are located in LD blocks enriched with circRNAs.
- circRNAs are suggested as potential novel contributors to the pathogenesis of multiple sclerosis.
- Further research into the role of circRNAs in MS is warranted to elucidate their functional significance.
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