Reworking GWAS Data to Understand the Role of Nongenetic Factors in MS Etiopathogenesis

Abstract

Genome-wide association studies have identified more than 200 multiple sclerosis (MS)-associated loci across the human genome over the last decade, suggesting complexity in the disease etiology. This complexity poses at least two challenges: the definition of an etiological model including the impact of nongenetic factors, and the clinical translation of genomic data that may be drivers for new druggable targets. We reviewed studies dealing with single genes of interest, to understand how MS-associated single nucleotide polymorphism (SNP) variants affect the expression and the function of those genes. We then surveyed studies on the bioinformatic reworking of genome-wide association studies (GWAS) data, with aggregate analyses of many GWAS loci, each contributing with a small effect to the overall disease predisposition. These investigations uncovered new information, especially when combined with nongenetic factors having possible roles in the disease etiology. In this context, the interactome approach, defined as “modules of genes whose products are known to physically interact with environmental or human factors with plausible relevance for MS pathogenesis”, will be reported in detail. For a future perspective, a polygenic risk score, defined as a cumulative risk derived from aggregating the contributions of many DNA variants associated with a complex trait, may be integrated with data on environmental factors affecting the disease risk or protection.

Prevention of MS Requires Intervention on the Causes of the Disease: Reconciling Genes, Epigenetics, and Epstein Barr Virus

“…For these reasons, using powerful but indirect methods (such as population genetics and immunology) to study the role of latent EBV in MS pathophysiology may yield valuable clues as to the nature of the pathology. Observations that many of the significant MS SNP-associations overlap with EBNA-2 transcription factor binding sites, for example, is interesting because this agrees with observations that anti-EBNA2 antibodies are part of the subset of EBV proteins that show a raised antibody profile in MS ( 23 , 76 – 79 ). If these studies are interpreted as converging on a role for EBNA-2, then this gives an insight into the nature of the dysregulation of latency, as EBNA-2 is an essential for regulating viral latent gene expression and for EBV-driving lymphocytes into the cell cycle.…”

Viruses and neuroinflammation in multiple sclerosis

“…Another level of complexity in the virus-host interplay is represented by the respective genomic variability. Single nucleotide polymorphisms (SNPs) have been associated with MS over time, and increasing evidence on this topic has been obtained thanks to genome-wide association studies [38][39][40] . This high-throughput approach led to the discovery (and in some cases confirmation) of SNPs located in DNA sequences coding for proteins or regulatory regions with a potential impact on gene expression and protein-protein interactions [41] .…”

Oxidative Stress Markers in Multiple Sclerosis

“…Most of the described associations, however, show a modest odds ratio (OR) and explain close to half of its heritability [ 1 , 2 ], HLA (in particular, the HLA-DRB1*15:01 haplotype) being the only one that has shown a strong association with MS risk [ 1 ]. It has been suggested that, together with genetic predisposition, some environmental factors, gene–environment, and environment–environment interactions, including smoking, infections (mainly Epstein–Barr virus seropositivity or exposure), low sun exposure/low vitamin D levels, and obesity may be related to the etiopathogenesis of MS and with MS onset and progression [ 3 , 4 , 5 ]. Since it has been suggested that oxidative stress is closely related to inflammation (for example, in inflammatory conditions, immune cells can liberate reactive oxidant substances leading to oxidative stress and, on the other hand, the oxidative damage produced by free radicals can induce an inflammatory response through the Toll-like receptors and inflammasomes) [ 6 , 7 ], with MS being a prototype of inflammatory diseases, oxidative stress could also play a role in the etiopathogenesis of MS. Figure 1 depicts the possible interaction between the different mechanisms proposed in the etiopathogenesis of MS, including oxidative stress.…”