Revealing the genetic basis of multiple sclerosis: are we there yet?

Abstract

For more than 30 years the only genetic factor associated with susceptibility to multiple sclerosis (MS) was the human leukocyte antigen (HLA) region. Recent advancements in genotyping platforms and the development of more effective statistical methods resulted in the identification of 16 more genes by genome-wide association studies (GWAS) in the last three years alone. While the effect of each of these genes is modest compared to that of HLA, this list is expected to grow significantly in the near future, thus defining a complex landscape in which susceptibility may be determined by a combination of allelic variants in different pathways according to ethnic background, disease sub-type, and specific environmental triggers. A considerable overlap of susceptibility genes among multiple autoimmune diseases is becoming evident and integration of these genetic variants with our current knowledge of affected biological pathways will greatly improve our understanding of mechanisms of general autoimmunity and of tissue specificity.

Figure 1. Autoimmune disease-gene network

Top genetic associations in 7 autoimmune diseases and T2D. The most significant SNP per gene was selected. Only associations with significance of at least p<10⁻⁴ are visualized. If a given gene was identified in more than one disease, multiple lines connecting it with each disease were drawn. Lines are colored using a “heat” scheme according to the evidence for association. Thus “hot” edges (e.g. red, orange) represent more significant associations than “cold” edges (e.g. purple, blue). Diseases are depicted by circles of size proportional to the number of associated genes, non-MHC genes by grey triangles. To facilitate visualization, only genes shared by at least two diseases are shown.