Association Studies In Multiple Sclerosis Research Articles

Field Synopsis and Re-analysis of Systematic Meta-analyses of Genetic Association Studies in Multiple Sclerosis: a Bayesian Approach.

To provide an up-to-date summary of multiple sclerosis-susceptible gene variants and assess the noteworthiness in hopes of finding true associations, we investigated the results of 44 meta-analyses on gene variants and multiple sclerosis published through December 2016. Out of 70 statistically significant genotype associations, roughly a fifth (21%) of the comparisons showed noteworthy false-positive rate probability (FPRP) at a statistical power to detect an OR of 1.5 and at a prior probability of 10-6 assumed for a random single nucleotide polymorphism. These associations (IRF8/rs17445836, STAT3/rs744166, HLA/rs4959093, HLA/rs2647046, HLA/rs7382297, HLA/rs17421624, HLA/rs2517646, HLA/rs9261491, HLA/rs2857439, HLA/rs16896944, HLA/rs3132671, HLA/rs2857435, HLA/rs9261471, HLA/rs2523393, HLA-DRB1/rs3135388, RGS1/rs2760524, PTGER4/rs9292777) also showed a noteworthy Bayesian false discovery probability (BFDP) and one additional association (CD24 rs8734/rs52812045) was also noteworthy via BFDP computation. Herein, we have identified several noteworthy biomarkers of multiple sclerosis susceptibility. We hope these data are used to study multiple sclerosis genetics and inform future screening programs.

Phenotype of Antigen Unexperienced TH Cells in the Inflamed Central Nervous System in Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis is a chronic, disseminated inflammation of the central nervous system which is thought to be driven by autoimmune T cells. Genetic association studies in multiple sclerosis and a large number of studies in the animal model of the disease support a role for effector/memory T helper cells. However, the mechanisms underlying relapses, remission and chronic progression in multiple sclerosis or the animal model experimental autoimmune encephalomyelitis, are not clear. In particular, there is only scarce information on the role of central nervous system-invading naive T helper cells in these processes. By applying two-photon laser scanning microscopy we could show in vivo that antigen unexperienced T helper cells migrated into the deep parenchyma of the inflamed central nervous system in experimental autoimmune encephalomyelitis, independent of their antigen specificity. Using flow cytometric analyses of central nervous system-derived lymphocytes we found that only antigen-specific, formerly naive T helper cells became activated during inflammation of the central nervous system encountering their corresponding antigen.

A new dawn for genetic association studies in multiple sclerosis.

Before the genomics technology revolution allowed us to do genome-wide science, genetics research relied on our limited knowledge about a subject to generate hypothesis and candidate genes to study. Despite the level of naiveté, several associations with susceptibility to a complex disease such as multiple sclerosis (MS) were discovered. Of these, HLA-DRB1 and IL7R (1) stand out as being confirmed and refined early by the genome-wide association studies (GWAS) that followed.(2) Despite the expense and gargantuan efforts, these GWAS have successfully led to the discovery of more than 100 additional genes, albeit with smaller effect sizes, that contribute to MS susceptibility.(3) This list keeps growing, but it comes with no surprise that most of these genes identified the immune system as one large candidate for MS susceptibility.

Genome-wide association studies in multiple sclerosis: lessons and future prospects

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease with complex aetiology. A haplotype within the major histocompatibility region is the major risk factor for MS, but despite clear evidence for a genetic component additional risk variants were not identified until the recent advent of genome-wide association studies (GWAS). At present, 10 GWAS have been conducted in MS, and together with follow-up studies these have confirmed 16 loci with genome-wide significance. Many of these common risk variants are located at or near genes with central immunological functions and the majority are associated with other autoimmune diseases. However, evidence from pathway analyses on more modestly associated variants also supports the involvement of neurological genes. Although the mechanisms by which the associated variants exert their effects are still poorly understood, some have been shown to correlate with expression of nearby genes. Further studies are required to define the functionally relevant variants in the identified regions and to investigate their effects at the molecular and cellular level. Finally, many genetic risk variants for MS remain to be identified. In order to expose some of the loci with more modest effects, a GWAS in nearly 10,000 MS patients has recently been completed.

Genes associated with multiple sclerosis: 15 and counting

Evaluation of: The International Multiple Sclerosis Genetics Consortium (IMSGC). IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. Genes Immun. 11(5), 397–405 (2010).Multiple sclerosis (MS) develops in genetically susceptible populations as a result of enviromental exposures, and discovering these genetic and/or environmental factors will provide fundamental new insights into the pathogenesis, diagnosis and treatment of this disabling disease. With the introduction of genome-wide association studies, the number of genes found to be associated with MS has increased rapidly. In all of these genes, in a study by the International Multiple Sclerosis Genetics Consortium, the classic MS risk locus, HLA-DRB1, stood out with remarkably strong statistical significance, but they also identified 12 other loci and/or genes associated with MS. However, all of these alleles have a very modest odds ratio and they explain approximately 3% of the variance in MS risk. Recently, the International Multiple Sclerosis Genetics Consortium provided evidence for three new loci that show significant association at a genome-wide level: RGS1, IL12A and MPHOSPH9/CDK2AP1. In this article, we will review the three newly discovered susceptibility loci and the implications of genome-wide association studies in MS on clinical practice.

The Effect of Single Nucleotide Polymorphisms from Genome Wide Association Studies in Multiple Sclerosis on Gene Expression

BackgroundMultiple sclerosis (MS) is a complex neurological disorder. Its aetiology involves both environmental and genetic factors. Recent genome-wide association studies have identified a number of single nucleotide polymorphisms (SNPs) associated with susceptibility to (MS). We investigated whether these genetic variations were associated with alteration in gene expression.Methods/Principal FindingsWe used a database of mRNA expression and genetic variation derived from immortalised peripheral lymphocytes to investigate polymorphisms associated with MS for correlation with gene expression. Several SNPs were found to be associated with changes in expression: in particular two with HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1, HLA-DRB4 and HLA-DRB5, one with ZFP57, one with CD58, two with IL7 and FAM164A, and one with FAM119B, TSFM and KUB3. We found minimal cross-over with a recent whole genome expression study in MS patients.DiscussionWe have shown that many susceptibility loci in MS are associated with changes in gene expression using an unbiased expression database. Several of these findings suggest novel gene candidates underlying the effects of MS-associated genetic variation.

Multiple sclerosis susceptibility-associated SNPs do not influence disease severity measures in a cohort of Australian MS patients.

Recent association studies in multiple sclerosis (MS) have identified and replicated several single nucleotide polymorphism (SNP) susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13–14 in addition to the well established allele HLA-DR15. There is potential that these genetic susceptibility factors could also modulate MS disease severity, as demonstrated previously for the MS risk allele HLA-DR15. We investigated this hypothesis in a cohort of 1006 well characterised MS patients from South-Eastern Australia. We tested the MS-associated SNPs for association with five measures of disease severity incorporating disability, age of onset, cognition and brain atrophy. We observed trends towards association between the RPL5 risk SNP and time between first demyelinating event and relapse, and between the CD40 risk SNP and symbol digit test score. No associations were significant after correction for multiple testing. We found no evidence for the hypothesis that these new MS disease risk-associated SNPs influence disease severity.

Pathway and network-based analysis of genome-wide association studies in multiple sclerosis

Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Typically, the number of markers in which the evidence for association exceeds the genome-wide significance threshold is very small, and markers that do not exceed this threshold are generally neglected. Classical statistical analysis of these datasets in MS revealed genes with known immunological functions. However, many of the markers showing modest association may represent false negatives. We hypothesize that certain combinations of genes flagged by these markers can be identified if they belong to a common biological pathway. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association (P < 0.05). Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance. These sub-networks, and others generated at random as a control, were categorized for membership of biological pathways. GWAS from eight other diseases were analyzed to assess the specificity of the pathways identified. In the MS datasets, we identified sub-networks of genes from several immunological pathways including cell adhesion, communication and signaling. Remarkably, neural pathways, namely axon-guidance and synaptic potentiation, were also over-represented in MS. In addition to the immunological pathways previously identified, we report here for the first time the potential involvement of neural pathways in MS susceptibility.

Genomewide association studies in multiple sclerosis, amyotrophic lateral sclerosis and restless legs syndrome

Genomewide association studies in multiple sclerosis, amyotrophic lateral sclerosis and restless legs syndrome

Association studies in multiple sclerosis

In the search for candidate loci having a role in susceptibility to common diseases such as multiple sclerosis (MS), studies often look for an ‘association’ between one allele at a putative candidate susceptibility locus and the disease, e.g. MS. However, reproducibility of results from association studies has been difficult. In MS, despite numerous studies, association has been reproducibly confirmed only for the major histocompatibility complex, the MHC. The present paper is designed to review the allelic associations which have been reported in MS and suggest possible reasons for the difficulties in replicating these studies. We also outline some suggestions for improving the validity of future association studies in MS and in other complex traits.