How Regulatory Variants Shape Multiple Sclerosis

The investigation of genetic variants in regulatory regions and their impact on complex diseases, particularly multiple sclerosis (MS), has garnered substantial attention in recent scientific research. In MS, most associated variants identified by genome-wide association studies (GWAS) are located in noncoding segments of the genome, concentrated mainly in regulatory regions. These regions are crucial for controlling gene expression and, consequently, can significantly influence disease development and progression.

A pivotal approach in understanding the regulatory function of these genetic variants in MS involves examining their enrichment in chromatin immunoprecipitation sequencing (ChIP-seq) peaks targeting key histone modifications. Studies have shown significant overlaps between MS GWAS signals and specific histone modification ChIP-seq peak regions, such as H3K27ac, H3K4me1, and H3K4me3. These modifications are indicative of active enhancers and promoters, suggesting that MS genetic risk associations are enriched at these regulatory elements. Particularly, B cells have been consistently identified as the cytotype displaying the highest enrichment in genetic signals.

Integrating genetic and 3D chromatin interaction data has also been instrumental in identifying putative causal genes in MS. Techniques like promoter capture Hi-C (PCHiC) and H3K4me3 HiChIP datasets have been used to update the roster of cell-specific susceptibility genes. This integration has led to the identification of a substantial number of genes across different cell types, including B cells, monocytes, and microglia.

Furthermore, colocalization analyses have revealed significant enrichment of MS-associated genetic variants in the transient transcriptome, particularly in regions coding for trRNAs. This association indicates a relationship between MS-associated GWAS signals and regulatory regions of DNA.

In addition, studies have analyzed protein connectivity among products of MS-associated loci. Proteins encoded by genes affected by genetic association signals are more likely to interact, often participating in the same biological pathways. This interconnectivity suggests that susceptibility to MS stems from a core of processes active in several immune-related cell types. These findings are in line with the “omnigenic” model of inheritance in complex diseases, which proposes that gene regulatory networks are interconnected to the extent that all genes expressed in disease-relevant cells could influence the functions of core disease-related genes.

In conclusion, the investigation of regulatory regions and genetic variants in MS has significantly advanced our understanding of the disease's etiology and progression. This research underscores the importance of a comprehensive approach that includes genetic, epigenomic, and transcriptomic analyses to unravel the complex regulatory networks underlying MS. These insights are not only crucial for understanding the disease mechanism but also pave the way for developing targeted therapeutic strategies.

Reference:

Ma, Q., Shams, H., Didonna, A., Baranzini, S. E., Cree, B. A., Hauser, S. L., ... & Oksenberg, J. R. (2023). Integration of epigenetic and genetic profiles identifies multiple sclerosis disease-critical cell types and genes. Communications Biology, 6(1), 342.
Umeton, R., Bellucci, G., Bigi, R., Romano, S., Buscarinu, M. C., Reniè, R., ... & Ristori, G. (2022). Multiple sclerosis genetic and non-genetic factors interact through the transient transcriptome. Scientific Reports, 12(1), 7536.
"A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis." Nature communications 10, no. 1 (2019): 2236.