Dataset Information

An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients.

ABSTRACT: Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease's estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes-particularly mRNA transport-or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family.

SUBMITTER: Barizzone N

PROVIDER: S-EPMC8535321 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients.

Barizzone Nadia N Cagliani Rachele R Basagni Chiara C Clarelli Ferdinando F Mendozzi Laura L Agliardi Cristina C Forni Diego D Tosi Martina M Mascia Elisabetta E Favero Francesco F Corà Davide D Corrado Lucia L Sorosina Melissa M Esposito Federica F Zuccalà Miriam M Vecchio Domizia D Liguori Maria M Comi Cristoforo C Comi Giancarlo G Martinelli Vittorio V Filippi Massimo M Leone Maurizio M Martinelli-Boneschi Filippo F Caputo Domenico D Sironi Manuela M Guerini Franca Rosa FR D'Alfonso Sandra S

Genes 20211013 10

Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease's estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respec ...[more]

PMID: 34681001

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Project description:BackgroundGenome-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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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.

Dataset Information

An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients.

Publications

An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients.

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