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Differential DNA methylation contributes to risk of multiple sclerosis

A recent study has discovered differentially methylated genomic regions harbouring 4 loci associated with risk of multiple sclerosis.

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system. In MS, demyelination occurs as the immune system attacks the myelin sheath surrounding neurons. This impairs the ability of neurons to transmit information. The exact causes of MS are still unclear, but a combination of genetic and environmental factors are known to influence risk. Genome-wide association studies have identified several small-effect loci contributing to MS risk. However, they do not account for the interplay between genetics and environmental exposure.

Epigenetics is a manifestation of gene-environment interactions, where environmental factors lead to changes in gene expression. A major epigenetic mechanism is DNA methylation. Its occurrence in regulatory regions can change gene expression levels and consequently alter cellular function. This can even influence disease risk. Accordingly, by identifying differentially methylated regions (DMRs) between affected and unaffected individuals may reveal new disease loci.  

MeDIP-seq

In this paper, published in the Journal of Neuroimmunology, researchers at the San Raffaele Scientific Institute investigated the whole-blood methylation profiles (methylomes) of MS-affected individuals and their relatives. They employed methylation immunoprecipitation sequencing (MeDIP-seq), a high-throughput approach that characterises the methylome on a genome-wide level.

The methylomes of 26 MS patients and 26 unaffected relatives from 8 Italian families were characterised by MeDIP-seq. Notably, the researchers applied stringent inclusion criteria, only selecting multiplex families with at least 3 MS-affected members. This allowed for better control over shared genetic and environmental factors compared to random case-control study designs.

Overall, comparison of the methylomes revealed 162 DMRs. Technical replication with targeted bisulfite sequencing and biological replication with MeDIP-seq in 2 additional families were performed to eliminate false positives. Ultimately, the researchers validated 4 novel DMRs to be associated with MS.

New epigenetic players in multiple sclerosis

Two of the verified DMRs were hypomethylated in MS-affected patients. They specifically mapped to regulatory regions of NTM and BAI3 genes that are involved in synaptic development. Hypomethylation is associated with elevated gene expression. Accordingly, the researchers speculated that abnormally high NTM and BAI3 expression in the brain may adversely affect neuronal development.

Meanwhile, the other two DMRs were hypermethylated and mapped to CALPN13 and PIK3R1. CALPN13 encodes calpain, a widely-expressed cysteine protease with potential demyelinating effects. PIK3R1 is involved in the metabolic action of insulin and has previously been identified as a candidate MS biomarker.

The contributions of these 4 genes needs to be validated in larger MS cohorts given the small sample size of this study. Still, the application of MeDIP-seq in multiplex families has enabled the discovery of novel DMRs.

By exploring epigenetics, this study has implicated novel genetic factors underlying MS risk. The application of epigenetics has made strides towards unravelling the intricacies behind MS and other complex diseases.

Image credit: kjpargeter – Freepik


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DNA Methylation / Epigenetics