Locus for severity implicates CNS resilience in progression of multiple sclerosis

In the paper

“These findings, together with the concordance for outcome within families7, suggest that an independent genetic architecture determines the clinical course of the disease”

What the sources say

• Supported

  The citation is attached to concordance for outcome within families, not to the citing authors’ subsequent inference about an independent genetic architecture. The Discussion (page not provided) reports that affected siblings tended to have similar ultimate disease courses, disability, and handicap scores. (LLM, conf=0.92)

  cites [7] Chataway, J. et al. Multiple sclerosis in sibling pairs: an analysis of 250 families. J. Neurol. Neurosurg. Psychiatry 71, 757–761 (2001). source

In the paper

“Although these risk variants have been found to reduce the age at onset5, it is notable that they do not appear to have any impact on disease severity6.”

What the sources say

• Supported

  The supplied passage labeled Abstract reports no evidence of genetic associations with disease severity. That supports the citing sentence’s qualified claim that MS susceptibility risk variants do not appear to affect severity. (LLM, conf=0.94)

  cites [5] International Multiple Sclerosis Genetics Consortium. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011). source
• Partly supported

  The Discussion (page unavailable) says that 52 established non-MHC MS risk variants were not convincingly shown to affect severity measured by MSSS. The claim extends that finding to susceptibility risk variants generally and to any impact on disease severity; the paper notes that modest effects and other severity outcomes remain possible. (LLM, conf=0.86)

  cites [6] George, M. F. et al. Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies. Neurol. Genet. 2, e87 (2016). sourceExperimental — accuracy not yet measured

In the paper

“In contrast, repeating the same analysis for MS susceptibility3 revealed strong enrichment in lymphoid organs, immune lymphoid and myeloid cells, as well as in tissues with recognized immunological functions and microbiota interactions (pharynx, lung, terminal ileum and endocervix; Fig. 1 and Supplementary Table 8).”

What the sources say

• Supported

  The Functional implications section (page not available) reports significant enrichment of MS susceptibility loci across immune cell types and tissues. It identifies T and B cells, innate immune cells, and the thymus, supporting the attributed immune-enrichment finding. The citing authors’ statement that they repeated an analysis describes their own work, not a result attributed to this source. (LLM, conf=0.87)

  cites [3] International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019). source

In the paper

“In contrast to immune-driven susceptibility3, these findings indicate a key role of CNS resilience and neurocognitive reserve in determining outcome in MS.”

What the sources say

• Supported

  The citation is attached to “immune-driven susceptibility,” not to the citing authors’ conclusion about CNS resilience and neurocognitive reserve. The Functional implications section reports enrichment of MS susceptibility loci in immune cell types, and the Discussion says MS may originate primarily in the peripheral immune compartment. (LLM, conf=0.94)

  cites [3] International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019). source

In the paper

“Partitioned heritability analysis by functional annotation with 53 categories14 did not identify strong enrichment in any category after correction for multiple testing (Supplementary Table 6), likely due to insufficient power.”

What the sources say

• Supported

  The citation is attached to the 53-category functional-annotation method, not to the citing authors’ finding of no strong enrichment. The source’s Results (Overview of methods) state that its full baseline model contains 53 overlapping functional categories. (LLM, conf=0.94)

  cites [14] Finucane, H. K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015). source

In the paper

“The lead variant rs10191329 (MAF = 0.17) was not close to (> 3 Mb) or in LD with (r2 ≤ 0.006) any of the lead MS susceptibility variants3.”

What the sources say

• ?Could not verify

  The Discovery and replication of genetic associations section reports MS susceptibility variants, but the passages do not identify rs10191329 or compare its distance or linkage disequilibrium with those variants. Searches for rs10191329 and the stated distance and LD values found no passage addressing that comparison. (LLM, conf=0.74)

  cites [3] International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019). sourceExperimental — accuracy not yet measured

In the paper

“This variant also displayed a methylation quantitative trait locus (QTL) effect in the promoter region of DYSF (ENSR00001922663) in the dorsolateral prefrontal cerebral cortex21 (Supplementary Table 13).”

What the sources say

• ?Could not verify

  The Introduction and Results > xQTL Discovery describe methylation QTL analyses in dorsolateral prefrontal cortex tissue. However, searches for rs10191329, DYSF, and ENSR00001922663 found no passage in our copy identifying the claimed variant–promoter methylation effect. (LLM, conf=0.72)

  cites [21] Ng, B. et al. An xQTL map integrates the genetic architecture of the human brain’s transcriptome and epigenome. Nat. Neurosci. 20, 1418–1426 (2017). sourceExperimental — accuracy not yet measured

In the paper

“The lead variant (rs149097173) did not overlap with known MS susceptibility loci3.”

What the sources say

• ?Could not verify

  The Discovery and replication of genetic associations section describes MS susceptibility regions and prioritized SNPs, but the retrieved passages do not mention rs149097173 or locate it relative to previously known loci. Searches for the variant identifier and for overlap with known loci did not establish the claimed non-overlap. (LLM, conf=0.72)

  cites [3] International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Statistical fine-mapping16 supported the replicated lead variants to be causal at their respective loci (rs10191329 posterior inclusion probability (PIP) = 0.75, rs149097173 PIP = 0.95; Supplementary Fig. 5).”

What the sources say

• Supported

  The citation is attached to “Statistical fine-mapping,” identifying the method used rather than attributing the two variant-specific results to the FINEMAP paper. The Discussion describes FINEMAP’s posterior probabilities and derived single-SNP inclusion probabilities. The rs10191329 and rs149097173 values are presented as results of the citing study, not results claimed to appear in this source. (LLM, conf=0.91)

  cites [16] Benner, C. et al. FINEMAP: efficient variable selection using summary data from genome-wide association studies. Bioinformatics 32, 1493–1501 (2016). source

In the paper

“Although not comparable in terms of likely mechanism, the magnitude of this effect matches that of treatment with a disease modifying agent such as beta-interferon35.”

What the sources say

• Supported

  The Results (Secondary outcomes; page not available in our copy) report a 4.0-year delay in reaching sustained EDSS 6.0, the walking-aid milestone, for the treated cohort versus untreated patients. The Introduction identifies beta-interferon as one of the disease-modifying treatments studied, so the paper supplies the treatment-effect magnitude used for the comparison; it does not give a beta-interferon-only estimate. (LLM, conf=0.88)

  cites [35] Palace, J. et al. Assessing the long-term effectiveness of interferon-beta and glatiramer acetate in multiple sclerosis: final 10-year results from the UK multiple sclerosis risk-sharing scheme. J. Neurol. Neurosurg. Psychiatry 90, 251–260 (2019). source

In the paper

“These prioritized genes were differentially expressed in MS brain lesion types relative to control white matter26,27 (Supplementary Note, Supplementary Fig. 6).”

What the sources say

• Partly supported

  The Methods section, ‘Differential expression analysis between MS Lesions and Control’ (page unavailable), describes a differential-expression analysis of oligodendrocyte-lineage cells. The passage comparing lesion types with control white matter (page unavailable) reports expression differences for several named genes. Our copy does not establish that those genes are the citing document’s ‘prioritized genes,’ so it supports the general finding but not that specific identification. (LLM, conf=0.84)

  cites [26] Jäkel, S. et al. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 566, 543–547 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The section “MIMS and AIMS at the chronic active lesion edge” reports genes differentially expressed at that edge relative to control white matter. Extended Data Fig. 9 also maps a list of prioritized MS susceptibility genes, but does not establish that the citing document’s prioritized genes were differentially expressed across MS lesion types. (LLM, conf=0.78)

  cites [27] Absinta, M. et al. A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature 597, 709–714 (2021). sourceExperimental — accuracy not yet measured

In the paper

“It may also partly explain why immunosuppressive therapies have thus far had little or no effect on disability accumulation in progressive MS trials4.”

What the sources say

• Supported

  The review’s Treating Progressive MS section reports that ocrelizumab reduces disability progression in primary progressive MS by approximately one-quarter. Its Conclusion says current therapies offer only partial protection against progression. This supports the citing sentence’s characterization of limited effects; the proposed explanation is the citing authors’ own framing. (LLM, conf=0.85)

  cites [4] Hauser, S. L. & Cree, B. A. C. Treatment of multiple sclerosis: a review. Am. J. Med. 133, 1380–1390.e2 (2020). source

In the paper

“This agrees with the inconclusive results of randomized trials of vitamin D supplementation in MS46 and a recent prospective study that found no association between BMI and clinical disability47.”

What the sources say

• Supported

  The Results section (Progression of MS, Sustained Clinical Progression on EDSS) reports no association between BMI and sustained clinical progression on the disability scale over 60 months. This supports the claim about clinical disability, specifically disability progression measured by EDSS in BENEFIT participants. (LLM, conf=0.92)

  cites [47] Manuel Escobar, J. et al. Body mass index as a predictor of MS activity and progression among participants in BENEFIT. Mult. Scler. 28, 1277–1285 (2022). source

In the paper

“Moreover, cell expression of ZNF638 was proportionally enriched in control brain tissue and chronic inactive MS lesions compared to other MS lesions26.”

What the sources say

• Partly supported

  The passage discussing lesion markers reports that the proportion of cells expressing several genes was enriched in control white matter and chronic inactive lesions, but not other lesions. It does not name ZNF638 among those genes, and a search for ZNF638 found no supporting passage in our copy. (LLM, conf=0.78)

  cites [26] Jäkel, S. et al. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 566, 543–547 (2019). sourceExperimental — accuracy not yet measured

In the paper

“In single-nucleus RNA sequencing from brain white matter areas in MS patients and controls, ZNF638 was preferentially expressed in an oligodendrocyte cluster with a predicted actively myelinating phenotype26.”

What the sources say

• Partly supported

  The paper reports single-nucleus RNA sequencing of white matter from controls and people with MS (Abstract; page unavailable). It also describes Oligo3 and Oligo4 as clusters predicted by gene-ontology analysis to be actively myelinating (Abstract; page unavailable). Our copy does not identify ZNF638 as preferentially expressed in either cluster, so the gene-specific finding is not supported. (LLM, conf=0.84)

  cites [26] Jäkel, S. et al. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 566, 543–547 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Although divergent genetic determinants of susceptibility and progression have been noted in other conditions8,9,36, the observation of distinct tissue enrichment is to our knowledge unique to MS.”

What the sources say

• Supported

  The citation supports the sentence’s background point that susceptibility and prognosis can have divergent genetic determinants in another condition. In the Abstract, the Crohn’s disease study reports prognosis-associated loci distinct from susceptibility loci. The sentence’s claim that distinct tissue enrichment is unique to MS is not attributed to this source. (LLM, conf=0.94)

  cites [8] Lee, J. C. et al. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn’s disease. Nat. Genet. 49, 262–268 (2017). source
• Supported

  The citation supports the sentence’s background clause about divergent genetic determinants in other conditions, not the citing authors’ conclusion about tissue enrichment in MS. The source reports in its Abstract that Parkinson’s disease variants associated with cognitive progression differed from susceptibility variants. (LLM, conf=0.93)

  cites [9] Liu, G. et al. Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease. Nat. Genet. 53, 787–793 (2021). source
• Supported

  Citation 36 supports the clause about divergent genetic determinants in another condition, not the citing authors’ claim that distinct tissue enrichment is unique to MS. In the Results section, the ALS paper reports that common genetic risk factors for susceptibility had limited effects on progression; its Discussion says susceptibility and disease modification can be distinct processes. The paper does not establish the MS uniqueness claim, but that claim is not attributed to this citation. (LLM, conf=0.91)

  cites [36] van Rheenen, W. et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat. Genet. 53, 1636–1648 (2021). source

In the paper

“Single nuclear RNA expression from 4 progressive MS patients and 5 non-neurological controls26 confirms PIGC expression in neuronal and glial cells including oligodendrocyte lineage cells.”

What the sources say

• Partly supported

  The paper reports single-nucleus RNA sequencing of white matter from four people with progressive MS and five non-neurological controls (Abstract; page unavailable). It identifies neuronal and glial cell clusters, including oligodendrocyte-lineage cells, but our copy does not report PIGC expression in those cells (searched: “PIGC” and a cell-type expression paraphrase). (LLM, conf=0.84)

  cites [26] Jäkel, S. et al. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature 566, 543–547 (2019). sourceExperimental — accuracy not yet measured

In the paper

“increasing brainstem and cortical pathology in brain tissue”

• Also stated in: § Severity locus impacts CNS tissue injury · plain

  “homozygous carriers displayed a 1.83-fold higher number of lesions in the brainstem (95% CI 1.09 to 3.06, P = 0.023; Methods), as well as a 1.76-fold higher rate of cortical lesions across sampled supratentorial tissue (95% CI 1.15 to 2.69, P = 0.001; Fig. 4)”

In the paper

“significant enrichment for expression in CNS tissues”

• Also stated in: § Heritability and tissue enrichment · plain

  “We observed a significant enrichment, adjusted for multiple testing, exclusively in CNS tissues across multiple brain regions and the C1 segment of the cervical spinal cord (Fig. 1 and Supplementary Table 7).”

In the paper

“We also identified suggestive association with rs149097173 in the DNM3-PIGC locus (P=2.3×10−7)”

• Also stated in: § Discovery of an MS severity locus · hedged

  “A suggestive association signal in the DNM3-PIGC locus replicated (P = 0.010) but did not reach genome-wide significance in the combined analysis (P = 2.3×10−7, Table 1).”

In the paper

“the risk allele shortening the median time to require a walking aid by up to 3.7 years”

• Also stated in: § Modifiers of longitudinal outcomes in MS · plain

  “In homozygous carriers, the lead variant also conferred a 3.7-year shorter median time to using a walking aid (EDSS 6.0; HR = 1.22, 95% CI 1.09–1.38, P = 9.3×10−4; Fig. 3c)”

In the paper

“Mendelian randomization analyses indicated a protective role for higher educational attainment.”

• Also stated in: § Education, smoking modulate MS severity · hedged

  “the main inverse-variance weighted MR estimate provided support for an association between higher years of education and milder MS severity (β = −0.15, PIVW = 0.005)”

In the paper

“We identified a significant association with rs10191329 in the DYSF-ZNF638 locus (P=3.6×10−9)”

• Also stated in: § Discovery of an MS severity locus · plain

  “The DYSF–ZNF638 locus was confirmed in the replication population and retained genome-wide significance in fixed-effects meta-analysis (P = 3.6×10−9, Table 1).”

In the paper

“The SNP-based heritability estimate (h2SNP) for variants with a MAF > 0.01 was 0.13 (s.e. 0.04) (Supplementary Table 5).”

In the paper

“Eleven additional loci showed suggestive association with ARMSS score (P < 5×10−6; Fig. 2), thereby identifying 12 independent loci that were brought forward for replication”

In the paper

“A generalized linear mixed model (LMM) analysis of serial EDSS across all visits revealed that DYSF–ZNF638 risk allele carriers displayed faster disability progression (P = 0.002; Fig. 3a).”

In the paper

“The ten other suggestive loci were not replicated.”

In the paper

“First, we observed only weak non-significant genetic correlation between MS severity and susceptibility (rg = 0.17, p = 0.25).”

In the paper

“We found a weak but statistically significant positive correlation with ARMSS score (incremental R2 = 0.001, P = 7.1×10−5) across MHC and non-MHC regions (Supplementary Fig. 8).”

In the paper

“A polygenic score (PGS) for MS severity was not associated with other neurological diseases in the UK Biobank (Supplementary Note).”

In the paper

“Conditional and joint analysis did not identify secondary signals.”

In the paper

“Even after adjusting for these indicators and their interactions, years of education remained associated with MS severity (Fig. 5b–e, Supplementary Tables 20 and 21, Methods).”

In the paper

“Carriage of the low frequency (MAF = 0.01) risk allele rs149097173T at the DNM3-PIGC locus was only nominally associated with accelerated disability accrual (P = 0.041)”

In the paper

“In addition, we examined rs10191329 and rs149097173 for their association with severity in African-American (n = 1,407) and Hispanic (n = 1,718) cohorts. Results were not significant, but the analysis was limited by a lack of statistical power owing to small sample size (median 28%) compounded by substantial imprecision in outcome measures”

In the paper

“Predicted expression of ZNF638 in the dorsolateral prefrontal cerebral cortex also associated with MS severity (Z = 3.1, P = 0.002; Methods).”

In the paper

“Next, the proportion of susceptibility variants showing concordant direction of effect in the severity GWAS was not different from that expected by chance (Pbinom = 0.097).”

In the paper

“Comparing individuals in the highest PGSMS quartile to those in the lowest, we detected no differences in their longitudinal outcomes (Extended Data Fig. 10).”

In the paper

“faster 24-week confirmed disability worsening (HR = 1.29, 95% CI 1.02–1.65, P = 0.037)”

In the paper

“the main inverse-variance weighted MR estimate provided support for an association between higher years of education and milder MS severity (β = −0.15, PIVW = 0.005)”

In the paper

“and between heavier smoking and worse MS severity (β = 0.23, PIVW = 0.005; Fig. 5a).”

In the paper

“Furthermore, none showed consistent nominal association (P < 0.05) across outcomes (Extended Data Fig. 9d).”

In the paper

“as well as a 1.76-fold higher rate of cortical lesions across sampled supratentorial tissue (95% CI 1.15 to 2.69, P = 0.001; Fig. 4)”

In the paper

“The association with education persisted in multivariable MR adjusting for smoking (β = −0.13, P = 0.04).”

In the paper

“adjusted Cox proportional hazards analyses showed that the risk allele rs10191329A at the DYSF–ZNF638 locus was associated with faster 24-week confirmed disability worsening (hazard ratio [HR] = 1.1 per unit increase in allele dosage, 95% CI 1.02–1.18, P = 7.9×10−3; Fig. 3b)”

In the paper

“Reverse analysis did not support an effect of genetic liability to MS severity on the traits considered (Supplementary Table 19).”

In the paper

“is preferentially expressed in the CNS, specifically in neurons and oligodendrocyte lineage cells (Extended Data Fig. 5 and 6).”

In the paper

“although a sensitivity analysis revealed a statistically significant association that withstood correction for multiple testing with time to sustained EDSS 6.0 (HR = 1.85, 95% CI 1.23 to 2.76, P = 0.0029; Methods)”

In the paper

“Individually, none of the variants influenced these outcomes after adjusting for the number tested (Extended Data Fig. 9a–c and Supplementary Table 22).”

In the paper

“we repeated this analysis adjusting for age at onset and observed that the effect of PGSMS on ARMSS score was substantially attenuated (incremental R2 = 3.9×10−4, P = 0.014; Supplementary Fig. 8).”

In the paper

“and a 3.3-year shorter median time to require a walking aid for risk allele carriers (for rs10191329, HR = 1.25, 95% CI 1.10 to 1.41, P = 0.0006).”

In the paper

“Genome-wide, we found no evidence of a shared genetic contribution between MS severity and a range of neurological, psychiatric, and autoimmune disorders.”

In the paper

“shorter time to EDSS 6.0 (HR = 1.56, 95% CI 1.05–2.34, P = 0.029; Extended Data Fig. 4)”

In the paper

“An association signal in the DYSF–ZNF638 locus reached genome-wide significance (P = 9.7×10−9; Fig. 2 and Table 1).”

In the paper

“In contrast, cognitive phenotypes and aging traits displayed inverse genetic correlations with MS severity (Extended Data Fig. 8 and Supplementary Table 17).”

In the paper

“Pathologically, homozygous carriers displayed a 1.83-fold higher number of lesions in the brainstem (95% CI 1.09 to 3.06, P = 0.023; Methods)”

In the paper

“This is further supported by negative genetic correlations with cognitive traits and aging, a factor previously implicated in MS progression immunology and neurobiology33.”

In the paper

“As with other prioritized genes, expression is preferentially in oligodendrocytes lineage cells and neurons.”

In the paper

“Moreover, the prioritized MS severity genes displayed shared cell type specificity in oligodendrocyte lineage cells.”

In the paper

“Our MR results do not support a causal role for serum 25OHD levels or BMI on MS severity.”

In the paper

“Our MR results do not support a causal role for serum 25OHD levels or BMI on MS severity.”

In the paper

“DYSF is also specifically expressed in oligodendrocytes and excitatory neurons, and the protein has been found to accumulate in Aβ-containing extracellular neuritic plaques, in proportion to Alzheimer’s disease severity44.”

In the paper

“The suggestive variant rs149097173 is located in intron 20 of DNM3, which encodes dynamin-3 and mediates synaptic vesicle endocytosis.”

In the paper

“The effect size was substantial, with 4 years of additional education (equivalent to an undergraduate degree) predicted to reduce disability rank by a quintile.”

In the paper

“no variant showed consistent association across three or more outcomes”

In the paper

“After removing population outliers, all remaining cases were of European ancestry.”

In the paper

“carriers had a 2.2-year shorter median time to require a walking aid”

In the paper

“Results were not significant after adjusting for multiple testing across two variants (see Fig. 3 for rs10191329 associations) and three outcomes (P < 0.05/6)”

In the paper

“We note that three of the genes show specificity for oligodendrocyte lineage cells.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Human Protein Atlas77

In the paper

“Across all analyses, the MS susceptibility PGS had no influence on longitudinal outcomes.”

In the paper

“Forest plots show successful replication of the two variants with minimal heterogeneity between centers as indicated by the Cochran’s Q and I2 statistics (n = 9,805 participants).”

In the paper

“confirming that the risk allele at the DYSF-ZNF638 locus is associated with worse injury at key brain locations.”

In the paper

“The direction of effect was consistent across all replication centers without evidence of heterogeneity (Q-statistic = 1.5, P = 0.99; I2 = 0%; Extended Data Fig. 3).”

In the paper

“In this GWAS, which included over 22,000 people with MS, we have identified the first genome-wide significant modifier of long-term outcome in MS”

In the paper

“These results were substantiated by pleiotropy-robust MR sensitivity analyses at different P value thresholds for instrument selection, in the absence of heterogeneity or outliers (Supplementary Table 19).”

In the paper

“We observed only modest inflation of the test statistics (λGC = 1.016; Supplementary Fig. 4)”

In the paper

“These results were not significant after correction for multiple testing (P > 0.05/6)”

In the paper

“Furthermore, we show that genetic susceptibility burden has little influence on cross-sectional and longitudinal outcomes outside of its effect on age at onset.”

In the paper

“In short, we found no evidence that susceptibility variants exert a meaningful effect on the outcome of the disease.”

In the paper

“Furthermore, convergent evidence supports a role, still to be determined, for ZNF638 in the CNS, including in the context of MS.”

In the paper

“Our findings demonstrate that at least 13% of the variance in long-term MS severity can be attributed to common and low frequency single nucleotide variation, explaining some of the considerable variability in MS outcome.”

In the paper

“The persistence of this association following adjustment for smoking and income may suggest direct biological effects.”

In the paper

“Our findings identify CNS resilience and reserve as likely determinants of MS progression, and may have broader implications for neurodegeneration.”

In the paper

“Results were unchanged when using a LMM or untransformed ARMSS scores (Supplementary Table 23).”

In the paper

“This strongly implicates neuronal and glial mechanisms as key determinants of MS progression”

In the paper

“In contrast, our results provide evidence for a causal effect of smoking on worsening disability, in line with strong observational evidence of faster disability progression in smokers that reverses following cessation48.”

In the paper

“This agrees with the inconclusive results of randomized trials of vitamin D supplementation in MS46 and a recent prospective study that found no association between BMI and clinical disability47.”

What the sources say

• ?Not checked — no full text of the sourcecites [46] Bhargava, P. et al. The vitamin D to ameliorate multiple sclerosis (VIDAMS) trial: study design for a multicenter, randomized, double-blind controlled trial of vitamin D in multiple sclerosis. Contemp. Clin. Trials 39, 288–293 (2014). source

In the paper

“Notably, this heritability was enriched in the brain and spinal cord, in marked contrast to the immune signal seen for MS susceptibility.”

In the paper

“In accordance with these data, we have found genetic support for educational attainment having a causal effect on reducing long-term MS severity.”

In the paper

“Here, we show that variation in genes preferentially expressed within the CNS modulate MS severity.”

In the paper

“Our gene prioritization analyses implicated four biologically plausible genes at the identified loci, including ZNF638 upstream of rs10191329.”

In the paper

“In conclusion, this study presents robust evidence for the role of genetic variation in influencing MS progression.”

In the paper

“Sensitivity analysis found no evidence of bias introduced by including participants who partially overlapped with the ARMSS score-based GWAS (Supplementary Note).”

In the paper

“The scree plots for our principal component analysis in the discovery (c) and replication (d) populations confirm that the first few principal components capture most of the variance attributable to the minimal population structure remaining after quality control.”