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Erschienen in: Journal of Neurology 11/2019

18.07.2019 | Original Communication

Integrative analysis revealed potential causal genetic and epigenetic factors for multiple sclerosis

verfasst von: Xing-Bo Mo, Shu-Feng Lei, Qi-Yu Qian, Yu-Fan Guo, Yong-Hong Zhang, Huan Zhang

Erschienen in: Journal of Neurology | Ausgabe 11/2019

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Abstract

Objective

Many genomic loci have been identified for multiple sclerosis (MS) by genome-wide association studies (GWAS). Discrimination of the most functionally relevant genes in these loci remains challenging. The aim of this study was to highlight potential causal genes for MS.

Methods

We detected potential causal DNA methylations and gene expressions for MS by integrating data from large scale GWAS and quantitative trait locus (QTL) studies using the summary data-based Mendelian randomization method. Potential functional SNPs in the identified genes were searched.

Results

We found 178 DNA methylation sites and mRNA expressions of 29 genes that were causally associated with MS. The identified genes enriched in 21 specific KEGG pathways and 80 GO terms (e.g., antigen processing and presentation, interferon gamma mediated signaling pathway). Among the identified non-MHC genes, METTL21B, METTL1 and TSFM were strongly connected. MS-associated SNPs in DDR1 were strongly associated with plasma MHC class I polypeptide-related sequence B (MICB) and Granzyme A levels. And plasma MICB and Granzyme A levels were causally associated with MS. Many SNPs in the causal genes showed QTL effects. The association between m6A-SNPs rs923829 and METTL21B expression level was validated in 40 unrelated Chinese Han individuals.

Conclusions

This study identified many DNA methylations and genes as important risk factors for MS and provided novel evidence on the association between circulating MICB and Granzyme A and MS. We also showed that the interaction among DDR1, MICB and GZMA and interaction among METTL21B, METTL1 and TSFM may participate in the pathogenesis of MS.
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Metadaten
Titel
Integrative analysis revealed potential causal genetic and epigenetic factors for multiple sclerosis
verfasst von
Xing-Bo Mo
Shu-Feng Lei
Qi-Yu Qian
Yu-Fan Guo
Yong-Hong Zhang
Huan Zhang
Publikationsdatum
18.07.2019
Verlag
Springer Berlin Heidelberg
Erschienen in
Journal of Neurology / Ausgabe 11/2019
Print ISSN: 0340-5354
Elektronische ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-019-09476-w

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