Multiple Sclerosis Risk Variants Research Articles

Disentangling the heterogeneity of multiple sclerosis through identification of independent neuropathological dimensions

Multiple sclerosis (MS) is a heterogeneous neurological disorder with regards to clinical presentation and pathophysiology. Here, we investigated the heterogeneity of MS by performing an exploratory factor analysis on quantitative and qualitative neuropathology data collected for 226 MS donors in the Netherlands Brain Bank autopsy cohort. Three promising dimensions were identified and subsequently validated with clinical, neuropathological, and genetic data. Dimension 1 ranged from a predominance of remyelinated and inactive lesions to extensive pathological changes, higher proportions of active and mixed lesions, and foamy microglia morphology. This pattern was positively correlated with more severe disease, the presence of B and T cells, and neuroaxonal damage. Scoring high on dimension 2 was associated with active lesions, reactive sites, and the presence of nodules. These donors had less severe disease, a specific pattern of cortical lesions, and MS risk variants in the human leukocyte antigen region, the latter indicating a connection between disease onset and this neuropathological dimension. Donors scoring high on dimension 3 showed increased lesional pathology with relatively more mixed and inactive lesions and ramified microglia morphology. This pattern was associated with longer disease duration, subpial cortical lesions, less involvement of the adaptive immune system, and less axonal damage. Taken together, the three dimensions may represent (1) demyelination and immune cell activity associated with pathological and clinical progression, (2) microglia (re)activity and possibly lesion initiation, and (3) loss of lesion activity and scar formation. Our findings highlight that a thorough understanding of the interplay between multiple pathological characteristics is crucial to understand the heterogeneity of MS pathology, as well as its association with genetic predictors and disease outcomes. The scores of donors on the dimensions can serve as an important starting point for further disentanglement of MS heterogeneity and translation into observations and interventions in living cohorts with MS.

Gene–environment interactions increase the risk of paediatric-onset multiple sclerosis associated with household chemical exposures

BackgroundWe previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis.MethodsUsing a case–control paediatric multiple sclerosis study, gene–environment interaction between exposure to household chemicals...

Expression of risk genes linked to vitamin D receptor super-enhancer regions and their association with phenotype severity in multiple sclerosis.

Multiple sclerosis (MS) is a chronic debilitating neurological condition with a wide range of phenotype variability. A complex interplay of genetic and environmental factors contributes to disease onset and progression in MS patients. Vitamin D deficiency is a known susceptibility factor for MS, however the underlying mechanism of vitamin D-gene interactions in MS etiology is still poorly understood. Vitamin D receptor super-enhancers (VSEs) are enriched in MS risk variants and may modulate these environment-gene interactions. mRNA expression in total of 64 patients with contrasting MS severity was quantified in select genes. First, RNA-seq was performed on a discovery cohort (10 mild, 10 severe MS phenotype) and ten genes regulated by VSEs that have been linked to MS risk were analyzed. Four candidates showed a significant positive association (GRINA, PLEC, PARP10, and LRG1) in the discovery cohort and were then quantified using digital droplet PCR (ddPCR) in a validation cohort (33 mild, 11 severe MS phenotype). A significant differential expression persisted in the validation cohort for three of the VSE-MS genes: GRINA (p = 0.0138), LRG1 (p = 0.0157), and PLEC (p = 0.0391). In summary, genes regulated by VSE regions that contain known MS risk variants were shown to have differential expression based on disease severity (p<0.05). The findings implicate a role for vitamin D super-enhancers in modulating disease activity. In addition, expression levels may have some utility as prognostic biomarkers in the future.

Multiple sclerosis risk variants influence the peripheral B-cell compartment early in life in the general population.

Multiple sclerosis (MS) is associated with abnormal B-cell function, and MS genetic risk alleles affect multiple genes that are expressed in B cells. However, how these genetic variants impact the B-cell compartment in early childhood is unclear. In the current study, we aim to assess whether polygenic risk scores (PRSs) for MS are associated with changes in the blood B-cell compartment in children from the general population. Six-year-old children from the population-based Generation R Study were included. Genotype data were used to calculate MS-PRSs and B-cell subset-enriched MS-PRSs, established by designating risk loci based on expression and function. Analyses of variance were performed to examine the effect of MS-PRSs on total B-cell numbers (n=1261) as well as naive and memory subsets (n=675). After correction for multiple testing, no significant associations were observed between MS-PRSs and total B-cell numbers and frequencies of subsets therein. A naive B-cell-MS-PRS (n=26 variants) was significantly associated with lower relative, but not absolute, naive B-cell numbers (p=1.03 × 10-4 and p=0.82, respectively), and higher frequencies and absolute numbers of CD27+ memory B cells (p=8.83 × 10-4 and p=4.89 × 10-3 , respectively). These associations remained significant after adjustment for Epstein-Barr virus seropositivity and the HLA-DRB1*15:01 genotype. The composition of the blood B-cell compartment is associated with specific naive B-cell-associated MS risk variants during childhood, possibly contributing to MS pathophysiology later in life. Cell subset-specific PRSs may offer a more sensitive tool to define the impact of genetic risk on the immune system in diseases such as MS.

Epigenetic control of ataxin-1 in multiple sclerosis.

Objective ATXN1 encodes the polyglutamine protein ataxin‐1, which we have demonstrated exerting an immunomodulatory function in the context of central nervous system (CNS) autoimmunity, in addition to its classical role in the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1). In this study, we dissected the contribution of DNA methylation to the regulation of ATXN1 in multiple sclerosis (MS).MethodsWe interrogated a DNA methylation dataset previously generated via bisulfate DNA sequencing (BS‐seq) in sorted peripheral immune cytotypes (CD4+ and CD8+ T cells, CD19+ B cells, and CD14+ monocytes) isolated from untreated MS patients at symptoms onset.ResultsHere, we report that ATXN1 undergoes hypo‐methylation at four distinct regions upon MS, exclusively in B cells. We also highlight how these differentially methylated sites overlap with other regulatory epigenetic marks and MS risk variants. Lastly, we employ luciferase assays to assess the functionality of these regions, showing that the loss of methylation leads to an increase in ATXN1 expression.InterpretationAltogether, these findings provide biological insights into ataxin‐1 regulation in the immune system as well as into the molecular mechanisms underlying MS risk.

Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55-IL6ST Gene Region in Immature Dendritic Cells.

Intronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS). The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4+ T lymphocytes of healthy controls. The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized. Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS). ANKRD55 was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent IL6ST, IL31RA, and SLC38A9 genes. Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4+ T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4+ T cells. MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype. We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626. Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo–DC) differentiation as a process potentially influenced by MS risk SNPs.

A higher burden of multiple sclerosis genetic risk confers an earlier onset

Background: Age at onset of multiple sclerosis (MS) is an objective, influential predictor of the evolution of MS independent of disease duration. Objectives: Determine the influence of MS genetic predisposition on age of onset. Methods: We conducted a comprehensive investigation of MS risk variants and age at onset in 3495 non-Latinx white individuals, including for combinations of HLA-DRB1*15:01 alleles and quintiles of an unweighted genetic risk score (GRS) for 198 of 200 autosomal MS risk variants that reside outside the major histocompatibility complex. Results: The mean age at onset was 32 years, 29% were male, and 46% were HLA-DRB1*15:01 carriers. For those with the greatest genetic risk burden (the highest GRS quintile with two HLA-DRB1*15:01 alleles) were on average 5 years younger at onset (p = 0.002) than those with the lowest genetic risk burden (the lowest GRS quintile with no HLA-DRB1*15:01 alleles). There was a strong inverse relationship between the MS genetic risk burden and age at onset of MS (p < 5 × 10−8). Conclusion: We demonstrate a significant gradient between elevated MS genetic risk burden and an earlier onset of MS, suggesting that a higher MS genetic risk burden accelerates onset of the disease.

T cell composition and polygenic multiple sclerosis risk: A population-based study in children.

Background and purposePatients with multiple sclerosis (MS) have altered T cell function and composition. Common genetic risk variants for MS affect proteins that function in the immune system. It is currently unclear to what extent T cell composition is affected by genetic risk factors for MS, and how this may precede a possible disease onset. Here, we aim to assess whether an MS polygenic risk score (PRS) is associated with an altered T cell composition in a large cohort of children from the general population.MethodsWe included genotyped participants from the population‐based Generation R study in whom immunophenotyping of blood T cells was performed at the age of 6 years. Analyses of variance were used to determine the impact of MS‐PRSs on total T cell numbers (n = 1261), CD4+ and CD8+ lineages, and subsets therein (n= 675). In addition, T‐cell‐specific PRSs were constructed based on functional pathway data.ResultsThe MS‐PRS negatively correlated with CD8+ T cell frequencies (p = 2.92 × 10−3), which resulted in a positive association with CD4+/CD8+ T cell ratios (p = 8.27 × 10−9). These associations were mainly driven by two of 195 genome‐wide significant MS risk variants: the main genetic risk variant for MS, HLA‐DRB1*15:01 and an HLA‐B risk variant. We observed no significant associations for the T‐cell‐specific PRSs.ConclusionsOur results suggest that MS‐associated genetic variants affect T cell composition during childhood in the general population.

Mining Complex Genetic Patterns Conferring Multiple Sclerosis Risk.

(1) Background: Complex genetic relationships, including gene-gene (G × G; epistasis), gene(n), and gene-environment (G × E) interactions, explain a substantial portion of the heritability in multiple sclerosis (MS). Machine learning and data mining methods are promising approaches for uncovering higher order genetic relationships, but their use in MS have been limited. (2) Methods: Association rule mining (ARM), a combinatorial rule-based machine learning algorithm, was applied to genetic data for non-Latinx MS cases (n = 207) and controls (n = 179). The objective was to identify patterns (rules) amongst the known MS risk variants, including HLA-DRB1*15:01 presence, HLA-A*02:01 absence, and 194 of the 200 common autosomal variants. Probabilistic measures (confidence and support) were used to mine rules. (3) Results: 114 rules met minimum requirements of 80% confidence and 5% support. The top ranking rule by confidence consisted of HLA-DRB1*15:01, SLC30A7-rs56678847 and AC093277.1-rs6880809; carriers of these variants had a significantly greater risk for MS (odds ratio = 20.2, 95% CI: 8.5, 37.5; p = 4 × 10−9). Several variants were shared across rules, the most common was INTS8-rs78727559, which was in 32.5% of rules. (4) Conclusions: In summary, we demonstrate evidence that specific combinations of MS risk variants disproportionately confer elevated risk by applying a robust analytical framework to a modestly sized study population.

Genetic factors for susceptibility to and manifestations of neuromyelitis optica.

ObjectiveTo identify genetic factors associated with susceptibility to and clinical features of neuromyelitis optica spectrum disorders (NMOSD).MethodsGenome‐wide single nucleotide polymorphism (SNP) genotyping was conducted in 211 Japanese patients with NMOSD fulfilling the 2006 criteria with or without anti‐aquaporin‐4 (AQP4) antibody and 1,919 Japanese healthy controls (HCs). HLA‐DRB1 and HLA‐DPB1 alleles were genotyped in 184 NMOSD cases and 317 HCs. Multiple sclerosis (MS) risk alleles outside the major histocompatibility complex (MHC) region were tested in NMOSD and MS genetic burden (MSGB) scores were compared between HCs and NMOSD.ResultsA SNP (rs1964995) in the MHC region was associated with NMOSD susceptibility (odds ratio (OR) = 2.33, P = 4.07 × 10−11). HLA‐DRB1*08:02 (OR = 2.86, P = 3.03 × 10−4) and HLA‐DRB1*16:02 (OR = 8.39, P = 1.92 × 10−3) were risk alleles for NMOSD susceptibility whereas HLA‐DRB1*09:01 was protective (OR = 0.27, P = 1.06 × 10−5). Three MS risk variants were associated with susceptibility and MSGB scores were significantly higher in NMOSD than in HCs (P = 0.0095). A SNP in the KCNMA1 (potassium calcium‐activated channel subfamily M alpha 1) gene was associated with disability score with genome‐wide significance (rs1516512, P = 2.33 × 10−8) and transverse myelitis (OR = 1.77, P = 0.011). KCNMA1 was immunohistochemically detected in the perivascular endfeet of astrocytes and its immunoreactivity was markedly diminished in active spinal cord lesions in NMOSD.InterpretationSpecific HLA‐DRB1 alleles confer NMOSD susceptibility and KCNMA1 is associated with disability and transverse myelitis in NMOSD.

Multiple sclerosis risk variants regulate gene expression in innate and adaptive immune cells.

At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS.

Replication analysis of variants associated with multiple sclerosis risk

Multiple Sclerosis (MS) is a complex chronic neurodegenerative disorder resulting from an autoimmune reaction against myelin. So far, many genetic variants have been reported to associate with MS risk however their association is inconsistent across different populations. Here we investigated the association of the most consistently reported genetic MS risk variants in the Kuwaiti MS population in a case-control study designs. Of the 94 reported MS risk variants four variants showed MS risk association in Arabs exome analysis (EVI5 rs11808092 p = 0.0002; TNFRSF1A rs1800693 p = 0.00003; MTHFR rs1801131 p = 0.038; and CD58 rs1414273 p = 0.00007). Replication analysis in Kuwaiti MS cases and healthy controls confirmed EVI5 rs11808092A (OR: 1.6, 95%CI: 1.19–2.16, p = 0.002) and MTHFR rs1801131G (OR: 1.79, 95%CI: 1.3–2.36, p = 0.001) as MS risk genetic factors, while TNFRSF1A rs1800693C had a marginal MS risk association (OR: 1.36, 95%CI: 1.04–1.78, p = 0.025) in the Kuwaiti population. CD58 rs1414273 did not sustain risk association (p = 0.37). In conclusion, EVI5 rs11808092A, TNFRSF1A rs1800693C and MTHFR rs1801131G are MS risk factors in the Kuwaiti population. Further investigations into their roles in MS pathogenesis and progression are merited.

Genetic roots of multiple sclerosis

Human Genomics The genetics underlying who develops multiple sclerosis (MS) have been difficult to work out. Examining more than 47,000 cases and 68,000 controls with multiple genome-wide association studies, the International Multiple Sclerosis Genetics Consortium identified more than 200 risk loci in MS (see the Perspective by Briggs). Focusing on the best candidate genes, including a model of the major histocompatibility complex region, the authors identified statistically independent effects at the genome level. Gene expression studies detected that every major immune cell type is enriched for MS susceptibility genes and that MS risk variants are enriched in brain-resident immune cells, especially microglia. Up to 48% of the genetic contribution of MS can be explained through this analysis. Science , this issue p. [eaav7188][1]; see also p. [1383][2] [1]: /lookup/doi/10.1126/science.aav7188 [2]: /lookup/doi/10.1126/science.aay1439

Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility.

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.

The genetic diversity of multiple sclerosis risk among Hispanic and African American populations living in the United States

Background: Substantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on Hispanic and African American populations within the United States. Objective: We sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex (n = 200) within these populations. Methods: Genotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses. Results: We found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene–environment or gene–gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability. Conclusion: These findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS.

Metabolome-based signature of disease pathology in MS

BackgroundDiagnostic delays are common for multiple sclerosis (MS) since diagnosis typically depends on the presentation of nonspecific clinical symptoms together with radiologically-determined central nervous system (CNS) lesions. It is important to reduce diagnostic delays as earlier initiation of disease modifying therapies mitigates long-term disability. Developing a metabolomic blood-based MS biomarker is attractive, but prior efforts have largely focused on specific subsets of metabolite classes or analytical platforms. Thus, there are opportunities to interrogate metabolite profiles using more expansive and comprehensive approaches for developing MS biomarkers and for advancing our understanding of MS pathogenesis. MethodsTo identify putative blood-based MS biomarkers, we comprehensively interrogated the metabolite profiles in 12 non-Hispanic white, non-smoking, male MS cases who were drug naïve for 3 months prior to biospecimen collection and 13 non-Hispanic white, non-smoking male controls who were frequency matched to cases by age and body mass index. We performed untargeted two-dimensional gas chromatography and time-of-flight mass spectrometry (GCxGC-TOFMS) and targeted lipidomic and amino acid analysis on serum. 325 metabolites met quality control and supervised machine learning was used to identify metabolites most informative for MS status. The discrimination potential of these select metabolites were assessed using receiver operator characteristic curves based on logistic models; top candidate metabolites were defined as having area under the curves (AUC) >80%. The associations between whole-genome expression data and the top candidate metabolites were examined, followed by pathway enrichment analyses. Similar associations were examined for 175 putative MS risk variants and the top candidate metabolites. Results12 metabolites were determined to be informative for MS status, of which 6 had AUCs >80%: pyroglutamate, laurate, acylcarnitine C14:1, N-methylmaleimide, and 2 phosphatidylcholines (PC ae 40:5, PC ae 42:5). These metabolites participate in glutathione metabolism, fatty acid metabolism/oxidation, cellular membrane composition, and transient receptor potential channel signaling. Pathway analyses based on the gene expression association for each metabolite suggested enrichment for pathways associated with apoptosis and mitochondrial dysfunction. Interestingly, the predominant MS genetic risk allele HLA-DRB1×15:01 was associated with one of the 6 top metabolites. ConclusionOur analysis represents the most comprehensive description of metabolic changes associated with MS in serum, to date, with the inclusion of genomic and genetic information. We identified atypical metabolic processes that differed between MS patients and controls, which may enable the development of biological targets for diagnosis and treatment.

WED 139 Gene expression regulation in CD4+ t-cell dysfunction in ms

BackgroundGenetic risk variants for complex disorders such as multiple sclerosis (MS) rarely encode protein. Growing evidence suggests risk variants regulate gene expression in specific disease-relevant cells by altering regulatory genetic sequences. This can be explored by correlating genotype at risk loci with expression of nearby genes (cis-regulation), with greatest sensitivity demonstrated in the most relevant cell types. Identifying genes under regulation by the MS risk variants could be a crucial step in identifying novel therapeutic targets.Aims1) Interrogate MS risk loci for cis-regulatory effects using allele-specific expression (ASE) analysis. 2) Establish a publicly available resource of genome-wide RNA-seq expression data in CSF-derived CD4 +T lymphocytes. 3) Correlate gene expression data with longitudinal clinical data to seek biomarkers of prognosis.Method and progressWe have extracted RNA from FACS-sorted CSF-derived CD4 +T lymphocytes from over 100 individuals. cDNA library preparation and sequencing for each sample is underway.Data analysisASE analysis makes use of a pre-selected transcribed SNP to differentiate maternal and paternal transcripts of each gene of interest. When an individual is heterozygous at an additional functional regulatory locus the ratio of maternal: paternal expression will deviate from 1:1. Each MS risk locus will be interrogated for this effect.

Multiple sclerosis risk variants alter expression of co-stimulatory genes in B cells.

The increasing evidence supporting a role for B cells in the pathogenesis of multiple sclerosis prompted us to investigate the influence of known susceptibility variants on the surface expression of co-stimulatory molecules in these cells. Using flow cytometry we measured surface expression of CD40 and CD86 in B cells from 68 patients and 162 healthy controls that were genotyped for the multiple sclerosis associated single nucleotide polymorphisms (SNPs) rs4810485, which maps within the CD40 gene, and rs9282641, which maps within the CD86 gene. We found that carrying the risk allele rs4810485*T lowered the cell-surface expression of CD40 in all tested B cell subtypes (in total B cells P ≤ 5.10 × 10-5 in patients and ≤4.09 × 10-6 in controls), while carrying the risk allele rs9282641*G increased the expression of CD86, with this effect primarily seen in the naïve B cell subset (P = 0.048 in patients and 5.38 × 10-5 in controls). In concordance with these results, analysis of RNA expression demonstrated that the risk allele rs4810485*T resulted in lower total CD40 expression (P = 0.057) but with an increased proportion of alternative splice-forms leading to decoy receptors (P = 4.00 × 10-7). Finally, we also observed that the risk allele rs4810485*T was associated with decreased levels of interleukin-10 (P = 0.020), which is considered to have an immunoregulatory function downstream of CD40. Given the importance of these co-stimulatory molecules in determining the immune reaction that appears in response to antigen our data suggest that B cells might have an important antigen presentation and immunoregulatory role in the pathogenesis of multiple sclerosis.

Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS.

To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS). We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820). Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01, and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model. We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.

Dysregulation of MS risk genes and pathways at distinct stages of disease.

Objective:To perform systematic transcriptomic analysis of multiple sclerosis (MS) risk genes in peripheral blood mononuclear cells (PBMCs) of subjects with distinct MS stages and describe the pathways characterized by dysregulated gene expressions.Methods:We monitored gene expression levels in PBMCs from 3 independent cohorts for a total of 297 cases (including clinically isolated syndromes (CIS), relapsing-remitting MS, primary and secondary progressive MS) and 96 healthy controls by distinct microarray platforms and quantitative PCR. Differential expression and pathway analyses for distinct MS stages were defined and validated by literature mining.Results:Genes located in the vicinity of MS risk variants displayed altered expression in peripheral blood at distinct stages of MS compared with the healthy population. The frequency of dysregulation was significantly higher than expected in CIS and progressive forms of MS. Pathway analysis for each MS stage–specific gene list showed that dysregulated genes contributed to pathogenic processes with scientific evidence in MS.Conclusions:Systematic gene expression analysis in PBMCs highlighted selective dysregulation of MS susceptibility genes playing a role in novel and well-known pathogenic pathways.