In silico prioritisation of microRNA-associated common variants in multiple sclerosis
Ifeolutembi A Fashina1,2,3, Claire E McCoy1, Simon J Furney4
1School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
Background:
Genome-wide association studies (GWAS) have highlighted over 200 autosomal variants associated with multiple sclerosis (MS). However, variants in non-coding regions such as those encoding microRNAs have not been explored thoroughly, despite strong evidence of microRNA dysregulation in MS patients and model organisms. This study explores the effect of microRNA-associated variants in MS, through the largest publicly available GWAS, which involved 47,429 MS cases and 68,374 controls.
Methods:
We identified SNPs within the coordinates of microRNAs, ± 5-kb microRNA flanking regions and predicted 3'UTR target-binding sites using miRBase v22, TargetScan 7.0 RNA22 v2.0 and dbSNP v151. We established the subset of microRNA-associated SNPs which were tested in the summary statistics of the largest MS GWAS by intersecting these datasets. Next, we prioritised those microRNA-associated SNPs which are among known MS susceptibility SNPs, are in strong linkage disequilibrium with the former or meet a microRNA-specific Bonferroni-corrected threshold. Finally, we predicted the effects of those prioritised SNPs on their microRNAs and 3'UTR target-binding sites using TargetScan v7.0, miRVaS and ADmiRE.
Results:
We have identified 30 candidate microRNA-associated variants which meet at least one of our prioritisation criteria. Among these, we highlighted one microRNA variant rs1414273 (MIR548AC) and four 3'UTR microRNA-binding site variants within SLC2A4RG (rs6742), CD27 (rs1059501), MMEL1 (rs881640) and BCL2L13 (rs2587100). We determined changes to the predicted microRNA stability and binding site recognition of these microRNA and target sites.
Conclusions:
We have systematically examined the functional, structural and regulatory effects of candidate MS variants among microRNAs and 3'UTR targets. This analysis allowed us to identify candidate microRNA-associated MS SNPs and highlights the value of prioritising non-coding RNA variation in GWAS. These candidate SNPs could influence microRNA regulation in MS patients. Our study is the first thorough investigation of both microRNA and 3'UTR target-binding site variation in multiple sclerosis using GWAS summary statistics.
Insights
This study investigated microRNA variants in multiple sclerosis (MS) using large genome-wide association studies (GWAS). We identified 30 candidate variants, highlighting their potential role in MS pathogenesis and non-coding RNA regulation.
Area of Science:
- Genetics
- Molecular Biology
- Neuroscience
Background:
- Genome-wide association studies (GWAS) have identified over 200 autosomal variants linked to multiple sclerosis (MS).
- MicroRNA (miRNA) dysregulation is implicated in MS, yet miRNA-associated variants remain underexplored.
- This research leverages the largest publicly available MS GWAS data (47,429 cases, 68,374 controls).
Purpose of the Study:
- To explore the impact of microRNA-associated variants on multiple sclerosis (MS) susceptibility.
- To identify and prioritize single nucleotide polymorphisms (SNPs) affecting miRNA function or their target binding sites.
- To investigate the role of non-coding RNA variation in MS pathogenesis.
Main Methods:
- Identified SNPs within miRNA coordinates, flanking regions, and predicted 3'UTR target sites using miRBase, TargetScan, RNA22, and dbSNP.
- Intersected miRNA-associated SNPs with MS GWAS summary statistics to identify candidate variants.
- Prioritized SNPs based on known MS associations, linkage disequilibrium, or miRNA-specific thresholds, and predicted their functional effects using TargetScan, miRVaS, and ADmiRE.
Main Results:
- Identified 30 candidate microRNA-associated variants meeting prioritization criteria.
- Highlighted specific variants: rs1414273 (MIR548AC) and 3'UTR binding site variants in SLC2A4RG (rs6742), CD27 (rs1059501), MMEL1 (rs881640), and BCL2L13 (rs2587100).
- Determined the predicted effects of these prioritized SNPs on miRNA stability and target recognition.
Conclusions:
- Systematically examined the functional, structural, and regulatory effects of candidate MS variants in miRNAs and their 3'UTR targets.
- Identified candidate microRNA-associated MS SNPs, emphasizing the value of prioritizing non-coding RNA variation in GWAS.
- These findings suggest that candidate SNPs may influence miRNA regulation in MS patients, representing the first comprehensive investigation of its kind in MS.
