Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk.

Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS

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.Cambridge NIHR Biomedical Research Centre UK MS Societ

Cell-based therapeutic strategies for multiple sclerosis.

The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials

Global, regional, and national burden of multiple sclerosis 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.

BACKGROUND: Multiple sclerosis is the most common inflammatory neurological disease in young adults. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic method of quantifying various effects of a given condition by demographic variables and geography. In this systematic analysis, we quantified the global burden of multiple sclerosis and its relationship with country development level. METHODS: We assessed the epidemiology of multiple sclerosis from 1990 to 2016. Epidemiological outcomes for multiple sclerosis were modelled with DisMod-MR version 2.1, a Bayesian meta-regression framework widely used in GBD epidemiological modelling. Assessment of multiple sclerosis as the cause of death was based on 13 110 site-years of vital registration data analysed in the GBD's cause of death ensemble modelling module, which is designed to choose the optimum combination of mathematical models and predictive covariates based on out-of-sample predictive validity testing. Data on prevalence and deaths are summarised in the indicator, disability-adjusted life-years (DALYs), which was calculated as the sum of years of life lost (YLLs) and years of life lived with a disability. We used the Socio-demographic Index, a composite indicator of income per person, years of education, and fertility, to assess relations with development level. FINDINGS: In 2016, there were 2 221 188 prevalent cases of multiple sclerosis (95% uncertainty interval [UI] 2 033 866-2 436 858) globally, which corresponded to a 10·4% (9·1 to 11·8) increase in the age-standardised prevalence since 1990. The highest age-standardised multiple sclerosis prevalence estimates per 100 000 population were in high-income North America (164·6, 95% UI, 153·2 to 177·1), western Europe (127·0, 115·4 to 139·6), and Australasia (91·1, 81·5 to 101·7), and the lowest were in eastern sub-Saharan Africa (3·3, 2·9-3·8), central sub-Saharan African (2·8, 2·4 to 3·1), and Oceania (2·0, 1·71 to 2·29). There were 18 932 deaths due to multiple sclerosis (95% UI 16 577 to 21 033) and 1 151 478 DALYs (968 605 to 1 345 776) due to multiple sclerosis in 2016. Globally, age-standardised death rates decreased significantly (change -11·5%, 95% UI -35·4 to -4·7), whereas the change in age-standardised DALYs was not significant (-4·2%, -16·4 to 0·8). YLLs due to premature death were greatest in the sixth decade of life (22·05, 95% UI 19·08 to 25·34). Changes in age-standardised DALYs assessed with the Socio-demographic Index between 1990 and 2016 were variable. INTERPRETATION: Multiple sclerosis is not common but is a potentially severe cause of neurological disability throughout adult life. Prevalence has increased substantially in many regions since 1990. These findings will be useful for resource allocation and planning in health services. Many regions worldwide have few or no epidemiological data on multiple sclerosis, and more studies are needed to make more accurate estimates. FUNDING: Bill & Melinda Gates Foundation

Neurophysiological corelates of fatigue and the feasibility of progressive resistance exercise for ameliorating symptoms of fatigue in people with multiple sclerosis

Clinicians are continually looking for effective treatments for multiple sclerosis (MS)- fatigue, but this has been hampered by unclear definitions of fatigue and studies of heterogeneous people with MS, including those who are highly-fatigued (MS-HF) and those who are less-fatigued (MS-LF). By directly comparing neuromuscular and transcranial magnetic stimulation measures between MS-HF and MS-LF, more light could be shed on the underpinning mechanisms of MS fatigue, and this could serve as a stronger foundation for therapeutic interventions. In addition, progressive resistance exercise has shown potential as an accessible exercise intervention for alleviating MS fatigue, but most studies have not recruited MS-HF or did not include MS fatigue as a primary outcome measure. In addition to positively impacting a range of other functional and mental health outcomes in PwMS, an individually tailored progressive resistance exercise (PRE) intervention has the potential to improve symptoms of fatigue and fatigability by helping to promote the development of new neural pathways (neuroplasticity). Thus, the overarching aim of this thesis was to establish whether neurophysiological differences between MS-HF and MS-LF could be reliably distinguished, and to investigate the feasibility and potential of PRE as a therapeutic exercise intervention for ameliorating perceived MS-fatigue in MS-HF. The series of investigations that set out to address this aim have led to many novel and interesting findings. Firstly, study 1 was the first systematic review and meta-analysis to synthesis the current evidence base comprising studies which used a dichotomised model (MS-HF versus MS-LF) to provide insights into structural and neurophysiological correlates of MS-fatigue. Secondly, Study 2 reports on the good to excellent test-retest reliability for a range of neuromuscular and transcranial magnetic stimulation measures assessed in the upper- and lower-limb muscles in MS-HF and MS-LF. Thirdly, based on the test-retest reliability findings of study 2, study 3 presents data for the differences between MS-HF compared to MS-LF and HC on a range of neuromuscular measures, including an isometric fatiguing exercise task in the upper- and lower-limb (performance fatigability measure). Finally, Study 4 presents important feasibility data regarding the utility of PRE as a therapeutic exercise option for MS-HF. In addition, this study provides preliminary evidence of the efficacy of PRE for ameliorating perceived MS-fatigue, a range of other patient-reported health outcomes and indices of neuromuscular function

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Peer reviewe

A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intraindividual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.Peer reviewe

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Peer reviewe