Multiple Sclerosis Susceptibility Research Articles

DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis

The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10−8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.

Aire is not essential for regulating neuroinflammatory disease in mice transgenic for human autoimmune-diseases associated MHC class II genes HLA-DR2b and HLA-DR4

The human autoimmune disease-associated HLA alleles HLA-DR2b (DRB1*1501) and HLA-DR4 (DRB1*0401) are strongly linked to increased susceptibility for multiple sclerosis (MS) and rheumatoid arthritis (RA), respectively. The underlying mechanisms are not fully understood, but these MHC alleles may shape the repertoire of pathogenic T cells via central tolerance. The transcription factor autoimmune regulator (AIRE) promotes central T cell tolerance via ectopic expression of tissue-specific antigens (TSAs). Aire deficiency in humans causes autoimmune polyendocrinopathy syndrome type 1 (APS1), and Aire knockout mice (Aire−/−) develop spontaneous autoimmune pathology characterized by multi-organ lymphocytic infiltrates.Here, we asked whether impaired TSAs gene expression in the absence of Aire promoted spontaneous MS- or RA-like autoimmune pathology in the context of human HLA alleles in HLA-DR2b or HLA-DR4 transgenic (tg) mice.The results show that reduced TSAs gene expression in the thymus of Aire-deficient HLA-DR2b or HLA-DR4 tg mice corresponded to mild spontaneous inflammatory infiltrates in salivary glands, liver, and pancreas. Moreover, Aire-deficiency modestly enhanced experimental autoimmune encephalomyelitis (EAE) in HLA-DR tg mice, but the animals did not show signs of spontaneous neuroinflammation or arthritis. No significant changes were observed in CD4+ T cell numbers, T cell receptor (TCR) distribution, regulatory T cells (Treg), or antigen-induced cytokine production. Abrogating Treg function by treatment with anti-CTLA-4 or anti-CD25 mAb in Aire-deficient HLA-DR tg mice did not trigger EAE or other autoimmune pathology. Our results suggest a redundant role for Aire in maintaining immune tolerance in the context of autoimmune disease-associated human HLA alleles.

Basal vitamin D levels and disease activity in multiple sclerosis patients treated with fingolimod.

Several studies have shown an association between 25-hydroxyvitamin D (25[OH]D) levels and multiple sclerosis (MS) susceptibility and/or level of disease activity in patients treated with first line drugs. To investigate whether baseline 25[OH]D values could influence disease activity also during treatment with the second-line drug fingolimod (FTY). We enrolled 176 MS patients who started FTY at the San Raffaele Hospital (OSR) MS center with available 25[OH]D measurement at the time of treatment start. We then prospectively followed them for 2years with periodic clinical examinations and MRI scans. We found no linear correlation between baseline 25[OH]D levels and annualized relapse rate (ARR) or time to first relapse. However, we observed that patients with serum 25[OH]D ≥ 100nmol/l showed a lower number of Gd+ and combined unique activity (CUA) lesions at baseline compared to patients with the lowest 25[OH]D levels (less than 50nmol/l, p value < 0.05). Moreover, they showed fewer CUA lesions at 2-year follow-up also when accounting for baseline level of disease activity (p value < 0.05). In patients treated with FTY, those with the highest baseline 25(OH)D levels had a significantly lower number of active lesions at baseline; the same effect, even if weaker, was observed also at 2-year follow-up when adjusting for baseline disease activity. Given Vitamin D supplementation safety profile, also if a causal effect has not yet been shown, most of MS patients could probably benefit from 25[OH]D levels above those currently considered to be sufficient.

CCR5Δ32 – A piece of protection in the inflammatory puzzle of multiple sclerosis susceptibility

BackgroundLeucocyte infiltration and activation in the central nervous system (CNS) is an important step in the pathogenesis of multiple sclerosis (MS). The Chemokine receptor 5 (CCR5) is implicated in immune cell migration and cytokine release in the CNS, and it was demonstrated to strongly contribute to CNS inflammation and damage in several models of sterile and pathogen-mediated CNS diseases. Although the inhibition of CCR5 results in a beneficial effect in experimental models of MS, conflicting results have been found about the loss-of-function variant CCR5Δ32 (rs333) in MS patients. The aim of this study was to evaluate the association of CCR5Δ32 and MS in a Brazilian case/control cohort. Patients and methods261 MS patients and 435 healthy controls were genotyped for CCR5Δ32. Allelic and genotypic frequencies were compared between patients and controls (case/control analysis), and among patients classified according to the MS clinical form (relapsing remitting versus progressive) and severity (EDSS, MSSS and progression index). Results and discussionThe CCR5Δ32 variant frequency was statistically higher in controls as compared to patients presenting European-derived ethnic background. The variant was more frequent in progressive MS as compared to RR-MS patients, and, although not statistically significant, a higher frequency of the truncated allele was observed among patients with less severe forms of MS. These findings emphasize the potential involvement of CCR5 signaling in CNS inflammation and damage in MS. ConclusionThe CCR5Δ32 deletion is a protective factor against the development and progression of MS in European-derived Brazilian patients.

Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis

Background: The association between HLA-DRB1*15:01 with multiple sclerosis (MS) susceptibility is well established, but the contribution of the tightly associated HLA-DRB5*01:01 allele has not yet been completely ascertained. Similarly, the effects of HLA-DRB1*04:01 alleles and haplotypes, defined at the full-gene resolution level with MS risk remains to be elucidated. Objectives: To characterize the molecular architecture of class II HLA-DR15 and HLA-DR4 haplotypes associated with MS. Methods: Next-generation sequencing was used to determine HLA-DQB1, HLA-DQA1, and HLA-DRB1/4/5 alleles in 1403 unrelated European-American patients and 1425 healthy unrelated controls. Effect sizes of HLA alleles and haplotypes on MS risk were measured by odds ratio (OR) with 95% confidence intervals. Results: HLA-DRB1*15:01:01:01SG (OR = 3.20, p < 2.2E–16), HLA-DRB5*01:01:01 (OR = 2.96, p < 2.2E–16), and HLA-DRB5*01:01:01v1_STR1 (OR = 8.18, p = 4.3E–05) alleles all occurred at significantly higher frequencies in MS patients compared to controls. The most significant predis-posing haplotypes were HLA-DQB1*06:02:01~HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01 and HLA-DQB1*06:02:01~HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01v1_STR1 (OR = 3.19, p < 2.2E–16; OR = 9.30, p = 9.7E–05, respectively). Analyses of the HLA-DRB1*04 cohort in the absence of HLA-DRB1*15:01 haplotypes revealed that the HLA-DQB1*03:01:01:01~HLA-DQA1*03:03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was protective (OR = 0.64, p = 0.028), whereas the HLA-DQB1*03:02:01~HLA-DQA1*03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was associated with MS susceptibility (OR = 1.66, p = 4.9E–03). Conclusion: HLA-DR15 haplotypes, including genomic variants of HLA-DRB5, and HLA-DR4 haplotypes affect MS risk.

Low cytomegalovirus seroprevalence in early multiple sclerosis: a case for the 'hygiene hypothesis'?

Cytomegalovirus (CMV) infection has recently been associated with a lower multiple sclerosis (MS) susceptibility, although it remains controversial whether it has a protective role or is merely an epiphenomenon related to westernization and early-life viral infections. We aimed to evaluate whether CMV serostatus may differ in patients with early MS as compared with patients with non-early MS, analyzing the putative association of this virus with MS clinical course and humoral immune responses against other herpesviruses. Multicentric analysis was undertaken of 310 patients with MS (early MS, disease duration ≤5years, n=127) and controls (n=155), evaluating specific humoral responses to CMV, Epstein-Barr virus and human herpesvirus-6, as well as T-cell and natural killer (NK)-cell immunophenotypes. Cytomegalovirus seroprevalence in early MS was lower than in non-early MS or controls (P<0.01), being independently associated with disease duration (odds ratio, 1.04; 95% confidence interval, 1.01-1.08, P<0.05). CMV+ patients with MS displayed increased proportions of differentiated T-cells (CD27-CD28-, CD57+, LILRB1+) and NKG2C+ NK-cells, which were associated with a lower disability in early MS (P<0.05). CMV+ patients with early MS had an age-related decline in serum anti-EBNA-1 antibodies (P<0.01), but no CMV-related differences in anti-human herpesvirus-6 humoral responses. Low CMV seroprevalence was observed in patients with early MS. Modification of MS risk attributed to CMV might be related to the induction of differentiated T-cell and NK-cell subsets and/or modulation of Epstein-Barr virus-specific immune responses at early stages of the disease.

Fish, Fatty Acid Biosynthesis Genes, and Multiple Sclerosis Susceptibility (S44.002)

Fish, Fatty Acid Biosynthesis Genes, and Multiple Sclerosis Susceptibility (S44.002)

Comparative analysis of RORA expression in brain tissue from multiple sclerosis and normal individuals:a pilot study

The key to understanding the autoimmune disease multiple sclerosis (MS) lies in a deeper analysis of the genes that play a role in the pathology of the disease. A new gene of interest encodes the retinoic acid receptor‐related orphan receptor alpha (RORA). This receptor is expressed in several tissues and plays a critical role in regulating inflammatory response, neuronal cell development, bone metabolism, and has been proposed to promote the differentiation of Th17 cells. Th17 cells play a role in initiating autoimmune central nervous system inflammation, which is the cause of this debilitating disease. To better understand the significance of RORA in MS, the focus of this study was to observe the expression of this receptor and determine its role in susceptibility of multiple sclerosis. We did so by isolating RNA from 10 brain samples, 5 from multiple sclerosis patients and 5 from healthy controls. We then subjected the RNA to quantitative RT‐PCR and normalized the samples to control RNAs TBP and GAPDH. We found that there was a significant increase in expression of RORA (P&lt;0.05) in brain samples from MS patients compared with healthy controls. This novel finding could be used as diagnostic criteria for susceptibility of multiple sclerosis and could potentially be a target for new treatments.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Impact of Five VDR Polymorphisms on Multiple Sclerosis Risk and Progression: a Case-Control and Genotype-Phenotype Study.

Vitamin D receptor polymorphisms have been the target of many studies focusing on multiple sclerosis. However, previously reported results have been inconclusive. The objective of this study was to investigate the association between five vitamin D receptor polymorphisms (EcoRV, FokI, ApaI, TaqI, and BsmI) and multiple sclerosis susceptibility and its course. The study was carried out as a case-control and genotype-phenotype study, consisted of 296 Czech multiple sclerosis patients and 135 healthy controls. Genotyping was carried out using polymerase chain reaction and restriction analysis. In multiple sclerosis men, allele and/or genotype distributions differed in EcoRV, TaqI, BsmI, and ApaI polymorphisms as compared to controls (EcoRV, pa = 0.02; Taq, pg = 0.02, pa = 0.02; BsmI, pg = 0.02, pa = 0.04; ApaI, pg = 0.008, pa = 0.005). In multiple sclerosis women, differences in the frequency of alleles and genotypes were found to be significant in ApaI (controls vs multiple sclerosis women: pg = 0.01, pa = 0.05). Conclusive results were observed between multiple sclerosis women in the case of EcoRV [differences in Expanded Disability Status Scale (p = 0.05); CT genotype was found to increase the risk of primary progressive multiple sclerosis 5.5 times (CT vs CC+TT pcorr = 0.01, sensitivity 0.833, specificity 0.525, power test 0.823)] and FokI [borderline difference in Multiple Sclerosis Severity Score (p = 0.05)]. Our results indicate that the distribution of investigated vitamin D receptor polymorphisms is a risk factor for multiple sclerosis susceptibility and progression in the Czech population. The association between disease risk and polymorphisms was found to be stronger in men. The association of disease progression with polymorphisms was observed only in women.

Highly conserved extended haplotypes of the major histocompatibility complex and their relationship to multiple sclerosis susceptibility.

ObjectiveTo determine the relationship between highly-conserved extended-haplotypes (CEHs) in the major histocompatibility complex (MHC) and MS-susceptibility.BackgroundAmong the ~200 MS-susceptibility regions, which are known from genome-wide analyses of single nucleotide polymorphisms (SNPs), the MHC accounts for roughly a third of the currently explained variance and the strongest MS-associations are for certain Class II alleles (e.g., HLA-DRB1*15:01; HLA-DRB1*03:01; and HLA-DRB1*13:03), which frequently reside on CEHs within the MHC.Design/MethodsAutosomal SNPs (441,547) from 11,376 MS cases and 18,872 controls in the WTCCC dataset were phased. The most significant MS associated SNP haplotype was composed of 11 SNPs in the MHC Class II region surrounding the HLA-DRB1 gene. We also phased alleles at the HLA-A, HLA-C, HLA-B, HLA-DRB1, and HLA-DQB1 loci. This data was used to probe the relationship between CEHs and MS susceptibility.ResultsWe phased a total of 59,884 extended haplotypes (HLA-A, HLA-C, HLA-B, HLA-DRB1, HLA-DQB1 and SNP haplotypes) from 29,942 individuals. Of these, 10,078 unique extended haplotypes were identified. The 10 most common CEHs accounted for 22% (13,302) of the total. By contrast, the 8,446 least common extended haplotypes also accounted for approximately 20% (12,298) of the total. This extreme frequency-disparity among extended haplotypes necessarily complicates interpretation of reported disease-associations with specific HLA alleles. In particular, the HLA motif HLA-DRB1*15:01~HLA-DQB1*06:02 is strongly associated with MS risk. Nevertheless, although this motif is almost always found on the a1 SNP haplotype, it can rarely be found on others (e.g., a27 and a36), and, in these cases, it seems to have no apparent disease-association (OR = 0.7; CI = 0.3–1.3 and OR = 0.7; CI = 0.2–2.2, respectively). Furthermore, single copy carriers of the a1 SNP-haplotype without this HLA motif still have an increased disease risk (OR = 2.2; CI = 1.2–3.8). In addition, even among the set of CEHs, which carry the Class II motif of HLA-DRB1*15:01~HLA-DQB1*06:02~a1, different CEHs have differing strengths in their MS-associations.ConclusionsThe MHC in diverse human populations consists, primarily, of a very small collection of very highly-selected CEHs. Our findings suggest that the MS-association with the HLA-DRB1*15:01~HLA-DQB1*06:02 haplotype may be due primarily to the combined attributes of the CEHs on which this particular HLA-motif often resides.

De novo vs. inherited copy number variations in multiple sclerosis susceptibility.

De novo vs. inherited copy number variations in multiple sclerosis susceptibility.

Genetic basis for relapse rate in multiple sclerosis: Association with LRP2 genetic variation

Background: In contrast to successes for multiple sclerosis (MS) susceptibility, the genetic basis for clinical heterogeneity remains largely unresolved. Objectives: We investigate the first reported genetic association with relapse rate. Methods: We genotyped variant rs12988804 in LRP2 in a homogeneous study population of 527 Belgian MS patients with 970 documented relapses. Results: The rs12988804*T allele is associated with a 1.16-fold increased hazard rate for a relapse occurring (P = 0.0078) and a higher baseline relapse rate prior to immunomodulatory treatment (P = 0.044). Conclusion: Variant rs12988804 in LRP2, the first example of a genome-wide significant association with relapse rate in MS, is replicated in an independent study.

Americas Committee for Treatment and Research in Multiple Sclerosis Forum 2017: Environmental factors, genetics, and epigenetics in MS susceptibility and clinical course

The Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2017 brought together a multidisciplinary team of basic and clinical researchers to discuss the impact of environmental, genetic, and epigenetic factors on multiple sclerosis (MS) susceptibility and clinical course. The series of articles in this special edition reflect the breadth and depth of the topics that were discussed.

Sex chromosome contributions to sex differences in multiple sclerosis susceptibility and progression

Background: Why are women more susceptible to multiple sclerosis, but men have worse disability progression? Sex differences in disease may be due to sex hormones, sex chromosomes, or both. Objective: Determine whether differences in sex chromosomes can contribute to sex differences in multiple sclerosis using experimental autoimmune encephalomyelitis. Methods: Sex chromosome transgenic mice, which permit the study of sex chromosomes not confounded by differences in sex hormones, were used to examine an effect of sex chromosomes on autoimmunity and neurodegeneration, focusing on X chromosome genes. Results: T-lymphocyte DNA methylation studies of the X chromosome gene Foxp3 suggested that maternal versus paternal imprinting of X chromosome genes may underlie sex differences in autoimmunity. Bone marrow chimeras with the same immune system but different sex chromosomes in the central nervous system suggested that differential expression of the X chromosome gene Toll-like receptor 7 in neurons may contribute to sex differences in neurodegeneration. Conclusion: Mapping the transcriptome and methylome in T lymphocytes and neurons in females versus males could reveal mechanisms underlying sex differences in autoimmunity and neurodegeneration.

Multiple sclerosis genetics

A broad scientific consensus has emerged linking multiple sclerosis (MS) risk to multiple independent and interacting DNA variants that are relatively frequent in the population and act in concert with environmental exposures. The multifactorial, polygenic model of heritability provided the rationale and impetus to pursue genome-wide association studies (GWAS), which have been highly successful in uncovering genetic variants influencing susceptibility. Over 200 loci have been firmly associated with MS susceptibility. The main association signal genome-wide maps to the major histocompatibility complex (MHC) gene cluster in chromosome 6p21. This association has been observed across all populations studied. However, a significant proportion of MS heritability remains unexplained. Decoding the genetics of MS represents a long-standing and important research goal in this disease, as the demonstration of even modest functional genomic effects on risk or the course of MS is likely to reveal fundamental disease mechanisms and possibly yield new therapeutic opportunities.

Thymic-Specific Serine Protease Limits Central Tolerance and Exacerbates Experimental Autoimmune Encephalomyelitis.

The genetic predisposition to multiple sclerosis (MS) is most strongly conveyed by MHC class II haplotypes, possibly by shaping the autoimmune CD4 T cell repertoire. Whether Ag-processing enzymes contribute to MS susceptibility by editing the peptide repertoire presented by these MHC haplotypes is unclear. Thymus-specific serine protease (TSSP) is expressed by thymic epithelial cells and thymic dendritic cells (DCs) and, in these two stromal compartments, TSSP edits the peptide repertoire presented by class II molecules. We show in this article that TSSP increases experimental autoimmune encephalomyelitis severity by limiting central tolerance to myelin oligodendrocyte glycoprotein. The effect on experimental autoimmune encephalomyelitis severity was MHC class II allele dependent, because the lack of TSSP expression conferred protection in NOD mice but not in C57BL/6 mice. Importantly, although human thymic DCs express TSSP, individuals segregate into two groups having a high or 10-fold lower level of expression. Therefore, the level of TSSP expression by thymic DCs may modify the risk factors for MS conferred by some MHC class II haplotypes.

Mapping of thalamic magnetic susceptibility in multiple sclerosis indicates decreasing iron with disease duration: A proposed mechanistic relationship between inflammation and oligodendrocyte vitality

Recent advances in susceptibility MRI have dramatically improved the visualization of deep gray matter brain regions and the quantification of their magnetic properties in vivo, providing a novel tool to study the poorly understood iron homeostasis in the human brain. In this study, we used an advanced combination of the recent quantitative susceptibility mapping technique with dedicated analysis methods to study intra-thalamic tissue alterations in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS). Thalamic pathology is one of the earliest hallmarks of MS and has been shown to correlate with cognitive dysfunction and fatigue, but the mechanisms underlying the thalamic pathology are poorly understood.We enrolled a total of 120 patients, 40 with CIS, 40 with Relapsing Remitting MS (RRMS), and 40 with Secondary Progressive MS (SPMS). For each of the three patient groups, we recruited 40 controls, group matched for age- and sex (120 total). We acquired quantitative susceptibility maps using a single-echo gradient echo MRI pulse sequence at 3 T. Group differences were studied by voxel-based analysis as well as with a custom thalamus atlas. We used threshold-free cluster enhancement (TFCE) and multiple regression analyses, respectively. We found significantly reduced magnetic susceptibility compared to controls in focal thalamic subregions of patients with RRMS (whole thalamus excluding the pulvinar nucleus) and SPMS (primarily pulvinar nucleus), but not in patients with CIS. Susceptibility reduction was significantly associated with disease duration in the pulvinar, the left lateral nuclear region, and the global thalamus. Susceptibility reduction indicates a decrease in tissue iron concentration suggesting an involvement of chronic microglia activation in the depletion of iron from oligodendrocytes in this central and integrative brain region. Not necessarily specific to MS, inflammation-mediated iron release may lead to a vicious circle that reduces the protection of axons and neuronal repair.

The multiple sclerosis risk allele within the AHI1 gene is associated with relapses in children and adults

BackgroundWhile common variant non-HLA (human leukocyte antigen) alleles have been associated with MS risk, their role in disease course is less clear. We sought to determine whether established multiple sclerosis (MS) genetic susceptibility factors are associated with relapse rate in children and an independent cohort of adults with MS. MethodsGenotyping was performed for 182 children with MS or clinically isolated syndrome with high risk for MS from two Pediatric MS Centers. They were prospectively followed for relapses. Fifty-two non-HLA MS susceptibility single nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate. Cox regression models were adjusted for sex, genetic ancestry, disease-modifying therapy (DMT), 25-OH vitamin D level and HLA-DRB1*15:01/03 status. Investigation of pediatric subject SNP results was performed using a second cohort of 141 adult MS subjects of Northern European ancestry from the Southern Tasmanian Multiple Sclerosis Longitudinal Study. ResultsFor pediatric subjects, 408 relapses were captured over 622 patient-years of follow-up. Four non-HLA risk SNPs (rs11154801, rs650258, rs12212193, rs2303759) were associated with relapses (p < 0.01) in the pediatric subjects. After adjustment for genetic ancestry, sex, age, vitamin D level, DMT use and HLA-DRB1*15 status, having two copies of the MS risk allele within AHI1 (rs11154801) was associated with increased relapses among children (HR = 1.75,95%CI = 1.18–2.48, p = 0.006) and this result was also observed among adults (HR = 1.81,95%CI = 1.05–3.03, p = 0.026). ConclusionsOur results suggest that the MS genetic risk variant within the gene AHI1 may contribute to disease course in addition to disease susceptibility.

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.

Spotlight on the September 26 issue

#### Notable in Neurology This issue features an article that analyzes gastrointestinal manifestations in patients with myotonic dystrophy types 1 and 2 and another that determines sex differences in the development of Alzheimer disease endophenotypes. A featured article investigates whether the manner of patient consent affects clinical characteristics of patients with stroke. ### Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility: A multiethnic study![Graphic][1]</img> This study highlights how multiethnic studies can provide insight into multiple sclerosis (MS) susceptibility. The authors found a strong and consistent association of Epstein-Barr virus antibody titers, but not cytomegalovirus, with … [1]: /embed/inline-graphic-1.gif