How genetics can help our understanding of MS

Disanto G, Sandve GK, Ricigliano VA, Pakpoor J, Berlanga-Taylor AJ, Handel AE, Kuhle J, Holden L, Watson CT, Giovannoni G, Handunnetthi L, Ramagopalan SV. DNase hypersensitive sites and association with multiple sclerosis. Hum Mol Genet. 2013 Oct [Epub ahead of print]

Genome wide association studies (GWAS) have shown that approximately 60 genetic variants influence the risk of developing multiple sclerosis (MS). Our aim was to identify the cell types in which these variants are active. We used available data on MS associated single nucleotide polymorphisms (SNPs) and deoxyribonuclease I hypersensitive sites (DHSs) from 112 different cell types. Genomic intervals were tested for overlap using the Genomic Hyperbrowser. The expression profile of the genes located nearby MS associated SNPs was assessed using the software GRAIL (Gene Relationships Across Implicated Loci). Genomic regions associated with MS were significantly enriched for a number of immune DHSs and in particular T helper (Th) 1, Th17, CD8+ cytotoxic T cells, CD19+ B cells and CD56+ natural killer (NK) cells (enrichment=2.34, 2.19, 2.27, 2.05 and 1.95 respectively; p<0.0001 for all of them). Similar results were obtained when genomic regions with suggestive association with MS and additional immune mediated traits were investigated. Several new candidate MS associated genes located within regions of suggestive association were identified by GRAIL (CARD11, FCRL2, CHST12, SYK, TCF7, SOCS1, NFKBIZ and NPAS1). Genetic data indicate that Th1, Th17, cytotoxic T, B and NK cells play a prominent role in the aetiology of MS. Regions with confirmed and suggestive association have a similar immunological profile indicating that many SNPs truly influencing the risk of MS actually fail to reach genome-wide significance. Finally, similar cell types are involved in the aetiology of other immune mediated diseases.

We know that there is a strong genetic component to MS risk and very recently 48 new MS-associated genetic variants were identified, bringing the total to 110.
All cells in the human body share the same DNA sequence, yet there are approximately 200 different types of cells in the human body. One way in which cells with identical DNA can have varying functions within the body and form part of different tissues is through the combination of DNA with proteins called histones, to form what we call chromatin. Alterations of these histones can result in the chromatin being “open” and the DNA sequence exposed, versus being “closed” and inactive. Regions where the chromatin is open enable transcription factors to bind and modify gene expression and the function of the cell. The location of these sites varies between different cell types and enables them to vary in function.
By using genome-wide maps showing where the chromatin is open in over 100 different cell types it was possible to determine in which cell types the chromatin is open where MS associated regions are found, and therefore likely to be active.
We found that the cell types with a very high activity in MS associated regions were cells involved in the immune system. The cell types indicated in this study to be particularly important in MS were Th1, Th17, CD8+ cytotoxic T cells and B cells. Interestingly, we found that brain tissues had the lowest level of activity in MS regions. This finding is important as there has been significant discussion over the years with regard to whether neurodegeneration in MS contributes to the cause of MS, or is a consequence of the disease process itself. These findings strongly suggest that MS is primarily an immune-mediated disease and that neurodegeneration is a secondary effect.
This study emphasises how genetic information can help further our understanding of MS. The same strategy can also be used to help elucidate disease causative cascades in other complex diseases!

Coi I am a co-author on this