Multiple Sclerosis Susceptibility Research Articles

Novel plasma and brain proteins that are implicated in multiple sclerosis.

Understanding how variations in the plasma and brain proteome contribute to multiple sclerosis susceptibility can provide important insights to guide drug repurposing and therapeutic development for the disease. However, the role of genetically predicted protein abundance in multiple sclerosis remains largely unknown. Integrating plasma proteomics (n = 3301) and brain proteomics (n = 376 discovery; n = 152 replication) into multiple sclerosis genome-wide association studies (n = 14 802 cases and 26 703 controls), we employed summary-based methods to identify candidate proteins involved in multiple sclerosis susceptibility. Next, we evaluated associations of the corresponding genes with multiple sclerosis at tissue-level using large gene expression quantitative trait data from whole-blood (n = 31 684) and brain (n = 1194) tissue. Further, to assess transcriptional profiles for candidate proteins at cell-level, we examined gene expression patterns in immune cell types (Dataset 1: n = 73 cases and 97 controls; Dataset 2: n = 31 cases and 31 controls) for identified plasma proteins, and in brain cell types (Dataset 1: n = 4 cases and 5 controls; Dataset 2: n = 5 cases and 3 controls) for identified brain proteins. In a longitudinal multiple sclerosis cohort (n = 203 cases followed up to 15 years), we also assessed the corresponding gene-level associations with the outcome of disability worsening. We identified 39 novel proteins associated with multiple sclerosis risk. Based on five identified plasma proteins, four available corresponding gene candidates showed consistent associations with multiple sclerosis risk in whole-blood, and we found TAPBPL upregulation in multiple sclerosis B cells, CD8+ T cells and natural killer cells compared with controls. Among the 34 candidate brain proteins, 18 were replicated in a smaller cohort and 14 of 21 available corresponding gene candidates also showed consistent associations with multiple sclerosis risk in brain tissue. In cell-specific analysis, six identified brain candidates showed consistent differential gene expression in neuron and oligodendrocyte cell clusters. Based on the 39 protein-coding genes, we found 23 genes that were associated with disability worsening in multiple sclerosis cases. The findings present a set of candidate protein biomarkers for multiple sclerosis, reinforced by high concordance in downstream transcriptomics findings at tissue-level. This study also highlights the heterogeneity of cell-specific transcriptional profiles for the identified proteins and that numerous candidates were also implicated in disease progression. Together, these findings can serve as an important anchor for future studies of disease mechanisms and therapeutic development.

Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis.

Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.

Towards a global view of multiple sclerosis genetics.

Multiple sclerosis (MS) is a neuroimmunological disorder of the CNS with a strong heritable component. The genetic architecture of MS susceptibility is well understood in populations of European ancestry. However, the extent to which this architecture explains MS susceptibility in populations of non-European ancestry remains unclear. In this Perspective article, we outline the scientific arguments for studying MS genetics in ancestrally diverse populations. We argue that this approach is likely to yield insights that could benefit individuals with MS from all ancestral groups. We explore the logistical and theoretical challenges that have held back this field to date and conclude that, despite these challenges, inclusion of participants of non-European ancestry in MS genetics studies will ultimately be of value to all patients with MS worldwide.

Impact of Multiple Sclerosis Risk Polymorphism rs7665090 on MANBA Activity, Lysosomal Endocytosis, and Lymphocyte Activation.

Deficiencies in Mannosidase β (MANBA) are associated with neurological abnormalities and recurrent infections. The single nucleotide polymorphism located in the 3′UTR of MANBA, rs7665090, was found to be associated with multiple sclerosis (MS) susceptibility. We aimed to study the functional impact of this polymorphism in lymphocytes isolated from MS patients and healthy controls. A total of 152 MS patients and 112 controls were genotyped for rs7665090. MANBA mRNA expression was quantified through qPCR and MANBA enzymatic activity was analyzed. Upon phytohemagglutinin stimulation, immune activation was evaluated by flow cytometry detection of CD69, endocytic function, and metabolic rates with Seahorse XFp Analyzer, and results were stratified by variation in rs7665090. A significantly reduced gene expression (p < 0.0001) and enzymatic activity (p = 0.018) of MANBA were found in lymphocytes of MS patients compared to those of controls. The rs7665090*GG genotype led to a significant β-mannosidase enzymatic deficiency correlated with lysosomal dysfunction, as well as decreased metabolic activation in lymphocytes of MS patients compared to those of rs7665090*GG controls. In contrast, lymphocytes of MS patients and controls carrying the homozygous AA genotype behaved similarly. Our work provides new evidence highlighting the impact of the MS-risk variant, rs7665090, and the role of MANBA in the immunopathology of MS.

X-linked genetic risk factors that promote autoimmunity and dampen remyelination are associated with multiple sclerosis susceptibility

BackgroundMultiple sclerosis (MS) is a chronic neurodegenerative disease, which has a strong genetic component and is more prevalent in women. MS is caused by an autoimmunity initiated inflammatory response which leads to axon demyelination, followed by axon loss, plaque formation and neurodegeneration. The goal of this article was to explore X-linked genetic factors that are associated with MS susceptibility. MethodsUsing UK Biobank microarray, we analyzed the prevalence of alleles on the X chromosome to identify variants potentially involved in MS. Overall, 488,225 patients across 18,857 markers were analyzed using PLINK. ResultsOur results identify 20 SNPs that are significantly more abundant in persons with MS. The genes associated with these SNPs belong to immunity (LAMP2, AVPR2, MTMR8, F8, BCOR, PORCN, and ELF4) and remyelination (NSDHL, HS6ST2, RBM10, TAZ, and AR) pathways that are potentially of great significance for understanding the onset and progression of multiple sclerosis. We further identified a significant 20-fold increase in incidence of MS cases in women with co-occurrences of SNPs associated with myelination and immunity functions. ConclusionsOur analysis provides novel insights into the roles of X-linked genes in the onset and presentation of multiple sclerosis, identifying 20 SNPs in 14 genes involved primarily in immunity and myelination functions that are significantly more abundant in persons with MS. Our co-occurrence analysis suggests that concurrent disruption of both myelination and immune systems significantly increases the risk of MS onset in women.

THE IMPACT OF VERY LATE ANTIGEN 4 POLYMORPHISM ON DRUG RESPONSIVENESS IN PATIENTS WITH MULTIPLE SCLEROSIS INITIATION

Background: Very late antigen 4 (VLA4) integrin facilitates the immune cells migration to central nervous system (CNS) through blood brain barrier (BBB), so the polymorphism in this gene may be considered as genetic risk factor for multiple sclerosis (MS) occurrence. It may interact with the responsiveness level of Natalizumab. Objective: To show if VLA4 single nucleotide gene polymorphism (SNP) (C-269-A) considered as genetic predisposition factor for MS and if have a role in Natalizumab (Tysabri) drug non-responsiveness. Methods: Sixty-six (66) person with MS and 60 healthy persons involved in this study, their ages were range from 14 to 67 years. They attended to seek treatment in the MS outpatient’s clinic, at Baghdad Teaching Hospital, Medical City Complex from December 2018 to March 2020. Patient were divided into two group; resistant group (34) and response group (32). The VLA-4 SNP polymorphism investigated by sequence specific primer polymerase chain reaction (SSP-PCR) technique. Results: The VLA4 gene SSP-PCR genotyping revealed no significant differences between patients and control group also between responder patients and non-responder to Natalizumab. Conclusion: VLA-4 polymorphisms at the level of SNP at positions 269 (C/A) have no role in MS susceptibility or Natalizumab responsiveness. Keywords: MS, Natalizumab, VLA-4 Citation: Khaliel AH, Abbas AA, Hatem AO, Abdulamir AS. The impact of Very Late Antigen 4 polymorphism on drug responsiveness in patients with multiple sclerosis initiation. Iraqi JMS. 2022; 20(1): 83-89. doi: 10.22578/IJMS.20.1.11

Study of ABO System and Multiple Sclerosis disease in Iraq

Multiple sclerosis (MS) is one of an autoimmune condition with uncertain etiopathology. According to new data, ABO system had played a role in the development and understanding numerous diseases. Lower level of 25-hydroxy vitamin D3 (25-OHD3) is considered as a risk factor for MS. The aims of this study is to identify the role of blood group distribution on the levels of parathyroid hormone (PTH), 25-OHD3, total calcium, inorganic phosphorus and total magnesium on MS patients. Additionally, we assessed the relation between Expanded Disability Status Scale (EDSS) and study parameters in patients. The Study included 107 patients with MS were distributed in to four groups according to their blood group (A, B, AB, and O). Additionally, 124 apparently healthy individuals as control group. Tukey analysis was showed the level of 25-OHD3 in patients with B+ was significant decrease than O+ and A+ patients group (P≤0.05). Furthermore, EDSS was negatively correlated with 25-OHD3 (P≤0.05) in B+ and O+ patient groups. Through this study, ABO group may be consider as a risk factor for MS susceptibility as another interesting variable.

GP.1 The genetic basis of multiple sclerosis severity

Background: The mechanisms underlying the severity and wide heterogeneity of multiple sclerosis (MS) remain poorly understood. A persistent challenge has been determining whether genetic variation influences these traits. Methods: In 12,584 people with MS (pwMS), we estimated the proportion of age-related MS severity score variance attributable to additive genetic variation (SNP-heritability). Then, we interrogated for enrichment in hundreds of tissues and cell types using gene expression annotations. We performed a genome-wide association study (GWAS) using 7.8 million variants and attempted replication in an independent cohort of 9,805 pwMS. A subset of 8,325 pwMS was examined longitudinally over 54,113 visits. Results: We observed a 10% SNP-heritability for MS severity. In contrast to MS susceptibility, robust tissue-level enrichment was apparent in the brain and cervical spinal cord, but not in immune cells. We identified a novel MS severity locus (p&lt;5×10−8) and confirmed this in the replicate population. The lead variant was associated with higher hazards of 6-month confirmed disability worsening (p=0.008) and faster EDSS worsening (p=0.002). Time to walking aid (EDSS 6.0) was 3.2 years earlier in homozygous risk carriers. Conclusions: This study identifies the first genetic modifier of MS progression, establishes the genetic contributions to its heterogeneity and describes a distinct genetic architecture from susceptibility.

The role of body fat in multiple sclerosis susceptibility and severity: A Mendelian randomisation study

Objective: The objective of this study was to explore the potential causal associations of body mass index, height, weight, fat mass, fat percentage and non-fat mass in the whole body, arms, legs and trunk (henceforth, ‘anthropometric measures’) with multiple sclerosis (MS) risk and severity. We also investigated the potential for reverse causation between anthropometric measures and MS risk. Methods: We conducted a two-sample univariable, multivariable and bidirectional Mendelian randomisation (MR) analysis. Results: A range of features linked to obesity (body mass index, weight, fat mass and fat percentage) were risk factors for MS development and worsened the disease’s severity in MS patients. Interestingly, we were able to demonstrate that height and non-fat mass have no association with MS risk or MS severity. We demonstrated that the association between anthropometric measures and MS is not subject to bias from reverse causation. Conclusions: Our findings provide evidence from human genetics that a range of features linked to obesity is an important contributor to MS development and MS severity, but height and non-fat mass are not. Importantly, these findings also identify a potentially modifiable factor that may reduce the accumulation of further disability and ameliorate MS severity.

A multi-step genomic approach prioritized TBKBP1 gene as relevant for multiple sclerosis susceptibility

BackgroundOver 200 genetic loci have been associated with multiple sclerosis (MS) explaining ~ 50% of its heritability, suggesting that additional mechanisms may account for the “missing heritability” phenomenon.ObjectiveTo analyze a large cohort of Italian individuals to identify markers associated with MS with potential functional impact in the disease.MethodsWe studied 2571 MS and 3234 healthy controls (HC) of continental Italian origin. Discovery phase included a genome wide association study (1727 MS, 2258 HC), with SNPs selected according to their association in the Italian cohort only or in a meta-analysis of signals with a cohort of European ancestry (4088 MS, 7144 HC). Top associated loci were then tested in two Italian cohorts through array-based genotyping (903 MS, 884 HC) and pool-based target sequencing (588 MS, 408 HC). Finally, functional prioritization through conditional eQTL and mQTL has been performed.ResultsTop associated signals overlap with already known MS loci on chromosomes 3 and 17. Three SNPs (rs4267364, rs8070463, rs67919208), all involved in the regulation of TBKBP1, were prioritized to be functionally relevant.ConclusionsNo evidence of novel signal of association with MS specific for the Italian continental population has been found; nevertheless, two MS loci seems to play a relevant role, raising the interest to further investigations for TBKBP1 gene.

Basal metabolic rate and risk of multiple sclerosis: a Mendelian randomization study.

To determine the relationship between basal metabolic rate (BMR) and multiple sclerosis (MS) susceptibility, we analyzed genome-wide association study (GWAS) summary statistics data from the International Multiple Sclerosis Genetics Consortium on a total of 115,803 participants of European descent, including 47,429 patients with MS and 68,374 controls. We selected 378 independent genetic variants strongly associated with BMR in a GWAS involving 454,874 participants as instrumental variables to examine a potential causal relationship between BMR and MS. A genetically predicted higher BMR was associated with a greater risk of MS (odds ratio [OR]: 1.283 per one standard deviation increase in BMR, 95% confidence interval [CI]: 1.108-1.486, P = 0.001). Moreover, we used the lasso method to eliminate heterogeneity (Q statistic = 384.58, P = 0.370). There was no pleiotropy in our study and no bias was found in the sensitivity analysis using the leave-one-out test. We provide novel evidence that a higher BMR is an independent causal risk factor in the development of MS. Further work is warranted to elucidate the potential mechanisms.

Age-specific effects of childhood body mass index on multiple sclerosis risk

ObjectiveHigher body mass index (BMI) during early life is thought to be a causal risk factor for multiple sclerosis (MS). We used longitudinal Mendelian randomisation (MR) to determine whether there is a critical window during which BMI influences MS risk.MethodsSummary statistics for childhood BMI (n ~ 28,000 children) and for MS susceptibility were obtained from recent large genome-wide association studies (GWAS) (n = 14,802 MS, 26,703 controls). We generated exposure instruments for BMI during four non-overlapping age epochs (< 3 months, 3 months–1.5 years, 2–5 years, and 7–8 years) and performed MR using the inverse variance weighted method with standard sensitivity analyses. Multivariable MR was used to account for effects mediated via later-life BMI.ResultsFor all age epochs other than birth, genetically determined higher BMI was associated with an increased liability to MS: Birth [Odds Ratio (OR) 0.81, 95% Confidence Interval (CI) 0.50–1.31, Number of Single-Nucleotide Polymorphisms (NSNPs) = 7, p = 0.39], Infancy (OR 1.18, 95% CI 1.04–1.33, NSNPs = 18, p = 0.01), Early childhood (OR 1.31, 95% CI 1.03–1.66, NSNPs = 4, p = 0.03), Later childhood (OR 1.34, 95% CI 1.08–1.66, NSNPs = 4, p = 0.01). Multivariable MR suggested that these effects may be mediated by effects on adult BMI.ConclusionWe provide evidence using MR that genetically determined higher BMI during early life is associated with increased MS risk. This effect may be driven by shared genetic architecture with later-life BMI.

The ZFP36 family of RNA-binding proteins regulate homeostatic and autoreactive T cell responses

Abstract The zinc finger 36 (ZFP36) family of RNA-binding proteins, consisting of ZFP36, ZFP36L1, and ZFP36L2, is known to negatively regulate mRNA stability and/or inhibit translation of many transcripts, including cytokines. While there are reports of all three family members regulating T cell cytokine production, delineating the functions of these genes is challenging due to spontaneous phenotypes upon global deletion of single genes and potential redundancy in their functions. To overcome this, we generated Cd4-Cre+ Zfp36fl/fl Zfp36l1fl/fl Zfp36l2fl/fl mice. Only upon triple deletion, but not individual or paired deletions, do mice spontaneously develop an inflammatory disease characterized by early lethality, hypercytokinemia, and immune cell infiltration into some peripheral organs, including the central nervous system. As SNPs in human ZFP36L1 and ZFP36L2 have been linked to susceptibility for multiple sclerosis, we tested ZFP36 family member individual and paired T cell-deficient mice in experimental autoimmune encephalomyelitis (EAE). To our surprise, Cd4-Cre+ Zfp36l1fl/fl Zfp36l2fl/fl mice were markedly protected from EAE clinical disease, while no change in disease severity was seen with any deletion strains involving Zfp36. There was a severe impairment in generating antigen-specific CD4+ T cells in Cd4-Cre+ Zfp36l1fl/fl Zfp36l2fl/fl mice during EAE priming. Our findings demonstrate a novel redundancy of the ZFP family members in regulating T cell homeostasis and a shared role for ZFP36L1 and ZFP36L2 to promote clonal expansion. Understanding the individual and shared functions of the ZFP36 family members may lead to opportunities to target them to suppress T cell-driven autoimmunity. M.E.C. supported by the National Science Foundation Graduate Research Fellowship program (DGE-1745038) and by grant 5T32AI007163 from the NIAID. B.T.E. supported by the NIAID (R01 AI113118).

Racial and Ethnic Disparities in Multiple Sclerosis Prevalence.

Background and ObjectivesThe goal of this work was to determine whether the prevalence of multiple sclerosis (MS) varies by race and ethnicity.MethodsWe conducted a retrospective cohort study of >2.6 million adults from the multiethnic, community-dwelling members of Kaiser Permanente Southern California. The complete electronic health records of individuals with at least 1 ICD-9 code for MS between January 1, 2008 and December 31, 2010 were reviewed. MS prevalence and 95% CIs stratified by age, sex, and race and ethnicity among 2010 members were estimated with binomial regression. Age- and sex-standardized prevalence was estimated according to the 2010 US Census population.ResultsWe identified 3,863 patients with MS. The average age of patients with prevalent MS was 51.7 years (SD 13.1 years), and 76.8% were women. The female preponderance was more pronounced among Black (81.2%) and Asian (83.6%) than White (76.3%) or Hispanic (74.5%) individuals with MS. Age- and sex-standardized MS prevalence per 100,000 was similarly high among Black (225.8, 95% CI 207.1–244.5) and White (237.7, 95% CI 228.2–247.2) and significantly lower among Hispanic (69.9, 95% CI 64.4–75.5) and Asian (22.6, 95% CI 17.1–28.1) persons. MS prevalence was highest between the ages of 35 and 64 years and declined after 65 years of age across all racial and ethnic groups. Among adults 18 to 24 years of age, the crude MS prevalence was low but was highest among Black and Hispanic young adults, lower in White people, and lowest in Asian/Pacific Islander individuals (48.5, 25.0, 18.0, and 7.1 per 100,000, respectively).DiscussionMS prevalence varies by race and ethnicity, being similarly high in White and Black and significantly lower in Hispanic and Asian persons in Southern California. Taken together with previous studies, these findings indicate that the burden of MS in the US Black community has long been underrecognized. More studies are needed to determine whether MS is an emerging disease among US Hispanic adults and whether MS susceptibility and prevalence vary among Hispanic or Asian individuals from different cultures or ancestral backgrounds.

Association of Latitude and Exposure to Ultraviolet B Radiation With Severity of Multiple Sclerosis: An International Registry Study.

The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS. This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS. The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, more severe disease was associated with higher latitudes (β = 0.08, 95% CI 0.04-0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (β = -0.02, 95% CI -0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (β = - 0.5, 95% CI -0.6 to 0.4) and 18 years (β = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (β = -1.0, 95% CI -1.1 to 0.9). In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.

Environmental risk factors in multiple sclerosis: bridging Mendelian randomization and observational studies.

Multiple sclerosis (MS) is a complex disease with both genetic variants and environmental factors involved in disease susceptibility. The main environmental risk factors associated with MS in observational studies include obesity, vitamin D deficiency, Epstein-Barr virus infection and smoking. As modifying these environmental and lifestyle factors may enable prevention, it is important to pinpoint causal links between these factors and MS. Leveraging genetics through the Mendelian randomization (MR) paradigm is an elegant way to inform prevention strategies in MS. In this review, we summarize MR studies regarding the impact of environmental factors on MS susceptibility, thereby paying attention to quality criteria which will aid readers in interpreting any MR studies. We draw parallels and differences with observational studies and randomized controlled trials and look forward to the challenges that such work presents going forward.

Lnc-HNF1A-AS1 and its target gene ATG5 is dysregulated in HLA-DRB1*15:01-negative female patients with multiple sclerosis

Human investigations and animal model studies have confirmed that autophagy process plays crucial roles in multiple sclerosis (MS) predisposition. In addition, the essential role of long noncoding RNAs (lncRNAs) in MS development has been recently reported. Current study aimed to investigate the expression level of lnc-HNF1A-AS1 as a new lncRNA and its target gene ATG5 in patients with MS. A total of 50 female patients with MS and 50 female healthy subjects were included in this observational case-control study. HLA-DRB1*15:01 allele, as a main risk factor for MS susceptibility, was ruled out in all included patients. The peripheral blood samples were obtained from all patients and total RNA was extracted and cDNA synthesis was performed. The gene expression level of lnc-HNF1A-AS1 and ATG5 was evaluated by Real-time quantitative PCR. Our results have shown that expression level of lnc-HNF1A-AS1 and ATG5 was significantly higher in total MS patients compared with controls (P-value = 0.0278 and P-value = 0.0064, respectively). In addition, there was statistically significant correlation between lnc-HNF1A-AS1 expression level with age of onset (r = 0.2937, P-value <0.05). Current study indicated abnormal up-regulation of two autophagy-related genes in the peripheral blood of HLA-DRB1*15:01-negative MS female patients compared with healthy controls. Therefore, autophagy-related mechanisms might be implicated in the pathobiology of MS in this subpopulation.

Polygenic risk score association with multiple sclerosis susceptibility and phenotype in Europeans.

Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the CNS. We developed polygenic risk scores (PRS) of multiple sclerosis and assessed associations with both disease status and severity in cohorts of European descent. The largest genome-wide association dataset for multiple sclerosis to date (n = 41 505) was leveraged to generate PRS scores, serving as an informative susceptibility marker, tested in two independent datasets, UK Biobank [area under the curve (AUC) = 0.73, 95% confidence interval (CI): 0.72-0.74, P = 6.41 × 10-146] and Kaiser Permanente in Northern California (KPNC, AUC = 0.8, 95% CI: 0.76-0.82, P = 1.5 × 10-53). Individuals within the top 10% of PRS were at higher than 5-fold increased risk in UK Biobank (95% CI: 4.7-6, P = 2.8 × 10-45) and 15-fold higher risk in KPNC (95% CI: 10.4-24, P = 3.7 × 10-11), relative to the median decile. The cumulative absolute risk of developing multiple sclerosis from age 20 onwards was significantly higher in genetically predisposed individuals according to PRS. Furthermore, inclusion of PRS in clinical risk models increased the risk discrimination by 13% to 26% over models based only on conventional risk factors in UK Biobank and KPNC, respectively. Stratifying disease risk by gene sets representative of curated cellular signalling cascades, nominated promising genetic candidate programmes for functional characterization. These pathways include inflammatory signalling mediation, response to viral infection, oxidative damage, RNA polymerase transcription, and epigenetic regulation of gene expression to be among significant contributors to multiple sclerosis susceptibility. This study also indicates that PRS is a useful measure for estimating susceptibility within related individuals in multicase families. We show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort (P < 0.001), consistent with a partial overlap between the genetics of susceptibility and end-organ tissue injury. Mendelian randomization analysis suggested an effect of multiple sclerosis susceptibility on thalamic volume, which was further indicated to be through horizontal pleiotropy rather than a causal effect. In summary, this study indicates important, replicable associations of PRS with enhanced risk assessment and radiographic outcomes of tissue injury, potentially informing targeted screening and prevention strategies.

Genetically predicted telomere length and multiple sclerosis

Previous epidemiological studies have indicated a role for telomere length in multiple sclerosis (MS) severity and phenotype. However, these studies failed to establish the causality between telomere length and MS susceptibility. Hence, we performed two-sample Mendelian randomization (MR) analysis to explore the causal relationship between telomere length and MS susceptibility. We used data of genetic variants associated with leukocyte telomere length as instrumental variables (IVs), which was identified from the largest and latest genome-wide association study (GWAS) from UK Biobank (UKB) with 472,174 participants. Summary data of MS was obtained from the International Multiple Sclerosis Genetics Consortium. We performed two-sample MR analyses using the inverse-variance weighted method as the primary approach. Other MR approaches, including the MR-Egger, the inverse variance weighted (multiplicative random effects), weighted median, simple median, weighted mode-based methods, and Causal Analysis Using Summary Effect estimates (CAUSE), were also conducted to detect the result robustness. The genetic liability to longer telomere length was associated with a higher risk of MS susceptibility (odds ratio [OR] per one-SD telomere length, 1.91; 95% confidence interval [CI], 1.48-2.47; P=8.04×10-7). The results remained consistent across multiple sensitivity analyses. Our study supports the causal relationship between longer telomere length and increased risk of MS susceptibility.

Human Herpesvirus 6A Is a Risk Factor for Multiple Sclerosis

The role for human herpesvirus (HHV)-6A or HHV-6B in multiple sclerosis (MS) pathogenesis has been controversial. Possibly because the damage of the virus infection may occur before onset of clinical symptoms and because it has been difficult to detect active infection and separate serological responses to HHV-6A or 6B. Recent studies report that in MS patients the serological response against HHV-6A is increased whereas it is decreased against HHV-6B. This effect seems to be even more pronounced in MS patients prior to diagnosis and supports previous studies postulating a predomination for HHV-6A in MS disease and suggests that the infection is important at early stages of the disease. Furthermore, HHV-6A infection interacts with other factors suspected of modulating MS susceptibility and progression such as infection with Epstein-Barr virus (EBV) and Cytomegalovirus (CMV), tobacco smoking, HLA alleles, UV irradiation and vitamin D levels. The multifactorial nature of MS and pathophysiological role for HHV-6A in inflammation and autoimmunity are discussed.