The DOI matches its Crossref record; 111 of the 115 references it cites were found in a registry or an index; 48 of the 61 sources its claims cite were checked for support.
Locus for severity implicates CNS resilience in progression of multiple sclerosis
Open accessPublished version of a preprint
Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults^ 1 , 2 . Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF–ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3–PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility^ 3 , these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS. A genome-wide association study including 22,389 cases of multiple sclerosis finds an association with disease progression at the DYSF–ZNF638 and DNM3–PIGC loci and identifies a potential of higher educational attainment in slowing disease progression.
Overview
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Written from the paper’s full text.
TL;DR
This genome-wide association study of multiple sclerosis severity in 12,584 discovery cases and 9,805 replication cases identified rs10191329 in the DYSF-ZNF638 locus as a genome-wide significant modifier of long-term disability. The findings implicate CNS resilience and neurocognitive reserve, rather than immune susceptibility, in MS progression.
Key findings
- rs10191329 in DYSF-ZNF638 reached genome-wide significance in meta-analysis (P = 3.6×10⁻⁹); the risk allele shortened median time to requiring a walking aid by up to 3.7 years and was associated with faster 24-week confirmed disability worsening (HR = 1.1, 95% CI 1.02–1.18, P = 7.9×10⁻³).
- Homozygous rs10191329 risk carriers had 1.83-fold more brainstem lesions (95% CI 1.09–3.06, P = 0.023) and a 1.76-fold higher rate of cortical lesions (95% CI 1.15–2.69, P = 0.001).
- rs149097173 in DNM3-PIGC showed suggestive association (P = 2.3×10⁻⁷) and replicated at P = 0.010 but did not reach genome-wide significance; it was associated with a 3.3-year shorter median time to requiring a walking aid in sensitivity analysis.
- SNP-based heritability for MS severity was 0.13 (s.e. 0.04), with significant enrichment exclusively in CNS tissues; Mendelian randomization supported higher educational attainment as protective (β = −0.15, P = 0.005) and heavier smoking as detrimental (β = 0.23, P = 0.005), with no causal role for 25-hydroxyvitamin D or BMI.
Methods
- Discovery GWAS used age-related MS severity score (ARMSS) in 12,584 European-ancestry MS cases from 21 cohorts, analyzing 7.8 million autosomal variants with MAF > 0.01; replication tested variants in 9,805 cases from nine independent cohorts, with fixed-effects meta-analysis.
- Longitudinal analyses included 8,325 patients with EDSS at three or more timepoints (54,113 visits up to 13.9 years), using generalized linear mixed models and Cox proportional hazards models for 24-week confirmed disability worsening and time to EDSS 6.0.
- Neuropathology analyses used 4,652 tissue blocks from 290 autopsy cases; additional analyses included LD score regression for heritability/tissue enrichment, fine-mapping, gene prioritization, polygenic scores, and two-sample Mendelian randomization for education, smoking, BMI, and 25-hydroxyvitamin D.
Limitations
- The paper states that EDSS has shortcomings including non-linear ordinal nature, rater variability, overemphasis on ambulation, and inadequate capture of cognitive impairment; survival events were observed only at clinic visits, not in real time.
- The paper notes that Mendelian randomization assumes linearity and may not apply at trait extremes, collider bias is possible, horizontal pleiotropy cannot be entirely excluded, and genetic predisposition for education/smoking may not equal environmental modification; broader social determinants were not tested.
- The text also makes evident that the autopsy cohort was too small for meaningful analysis of rs149097173, and the African-American and Hispanic analyses were underpowered and imprecise.
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Claims the paper makes
60 Own result · 25 Own interpretation · 20 Supported · 16 Own method · 13 Partly supported · 7 No full text of the sources · 4 Couldn’t confirm · 3 Sources not found · 2 Supported so far · 2 Not checked yet · 1 No basis given · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
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”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > INTRODUCTION
What the sources say
- Supportedcites [7] Chataway, J. et al. Multiple sclerosis in sibling pairs: an analysis of 250 families. J. Neurol. Neurosurg. Psychiatry 71, 757–761 (2001). source
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)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
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.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > INTRODUCTION
What the sources say
- Supportedcites [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
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)
- Partly supportedcites [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
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)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
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).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Heritability and tissue enrichment
What the sources say
- Supportedcites [3] International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019). source
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)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
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.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > Abstract
What the sources say
- Supportedcites [3] International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019). source
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)
hedgeddirectn = 12,584- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
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.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Heritability and tissue enrichment
What the sources say
- Supportedcites [14] Finucane, H. K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015). source
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)
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
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.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Discovery of an MS severity locus
What the sources say
- Could not verifycites [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
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources that could be checked couldn’t confirm or dispute this claim.
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).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Gene prioritization and related traits
What the sources say
- Could not verifycites [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
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Could not verify
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“The lead variant (rs149097173) did not overlap with known MS susceptibility loci3.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Discovery of an MS severity locus
What the sources say
- Could not verifycites [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
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
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).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Discovery of an MS severity locus
What the sources say
- Supportedcites [16] Benner, C. et al. FINEMAP: efficient variable selection using summary data from genome-wide association studies. Bioinformatics 32, 1493–1501 (2016). source
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Supported
Every source the paper cites for this claim was checked and supports it.
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.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Supportedcites [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
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)
plaincorrelationaln = 22,000- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
- It may state two separate claims as one. 33
- Probably not a substantial claim. 38
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“published efforts to systematically interrogate severity have, thus far, only involved modest numbers of cases, and unanimously fall short of identifying any convincingly associated genetic variants5,10,11.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > INTRODUCTION
What the sources say
- Partly supportedcites [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). sourceExperimental — accuracy not yet measured
The paper reports that its analysis found no evidence of genetic associations with MS severity (Abstract; page unavailable), supporting the claim about the absence of convincing variants in this study. It does not establish that published severity studies involved only modest numbers of cases; its reference to modestly powered studies concerns disease susceptibility, not severity. (LLM, conf=0.86)
- Supportedcites [10] International Multiple Sclerosis Genetics Consortium. Genome-wide association study of severity in multiple sclerosis. Genes Immun. 12, 615–625 (2011). source
The Discussion describes earlier investigations of MS progression and severity as limited by small sample sizes. The Introduction says there was no confirmed MS severity locus, and the Abstract reports that no result in this study of 1,470 cases reached genome-wide significance. (LLM, conf=0.92)
- Partly supportedcites [11] International Multiple Sclerosis Genetics Consortium. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat. Genet. 45, 1353–1360 (2013). sourceExperimental — accuracy not yet measured
Online Methods, ‘Secondary analyses’ (page unavailable), confirms that this paper performed a case-only analysis of MS severity using MSSS. Our copy does not give the number of cases in that analysis or report whether it identified any convincingly associated variants, so it does not substantiate those parts of the claim. (LLM, conf=0.78)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Besides these clinical differences, homozygous rs10191329 risk allele carriers also demonstrated more severe MS-specific brainstem and cortical pathology, which result in axonal and neuronal degeneration respectively and drive progression18,19.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Partly supportedcites [18] Schirmer, L. et al. Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature 573, 75–82 (2019). sourceExperimental — accuracy not yet measured
The Results report degeneration and selective loss of upper-layer excitatory neurons in cortical MS lesions, and the Discussion links cortical neurodegeneration to regions involved in progression. The paper does not establish that homozygous rs10191329 carriers have more severe pathology, nor does it report brainstem pathology or show that these changes drive progression. (LLM, conf=0.87)
- Partly supportedcites [19] Absinta, M., Lassmann, H. & Trapp, B. D. Mechanisms underlying progression in multiple sclerosis. Curr. Opin. Neurol. 33, 277–285 (2020). sourceExperimental — accuracy not yet measured
The 'Neuropathology of progressive MS' section links cortical lesions to disability, and 'Final pathways of neuro-axonal dysfunction and death' discusses axonal degeneration and cortical neuronal loss (page numbers unavailable). But the paper does not report that homozygous rs10191329 risk-allele carriers have more severe brainstem or cortical pathology, nor does it link brainstem pathology specifically to their axonal degeneration. (LLM, conf=0.86)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Integrated analysis of genetically regulated and compound-perturbed gene expression28 revealed significant enrichment for CNS-acting compounds and, along with an alternative locus-based approach, identified chromatin remodeling via histone deacetylase inhibitors as a potential therapeutic strategy for slowing progression”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Gene prioritization and related traits
What the sources say
- Partly supportedcites [28] Konuma, T., Ogawa, K. & Okada, Y. Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates. Hum. Mol. Genet. 30, 294–304 (2021). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“DYSF is implicated in membrane repair22; ZNF638 mediates the silencing of unintegrated viral DNA23.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Gene prioritization and related traits
What the sources say
- Not checked — no full text of the sourcecites [22] Bansal, D. et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168–172 (2003). source
- Supportedcites [23] Zhu, Y., Wang, G. Z., Cingöz, O. & Goff, S. P. NP220 mediates silencing of unintegrated retroviral DNA. Nature 564, 278–282 (2018). source
The paper identifies NP220 as ZNF638 in the Abstract, then reports that NP220 is required to silence unintegrated retroviral DNA. The DYSF clause has a different citation and is not attributed to this source. (LLM, conf=0.94)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“DNM3 participates in the morphogenesis of the postsynaptic density and excitatory synaptic transmission24”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Gene prioritization and related traits
What the sources say
- Partly supportedcites [24] Lu, J. et al. Postsynaptic positioning of endocytic zones and AMPA receptor cycling by physical coupling of dynamin-3 to Homer. Neuron 55, 874–889 (2007). sourceExperimental — accuracy not yet measured
The section “The Endocytic Zone Sustains Excitatory Synaptic Transmission” (p. 9) reports that dynamin-3 knockdown reduces excitatory postsynaptic currents, supporting its role in excitatory transmission. The paper shows dynamin-3 positions the endocytic zone near the postsynaptic density (p. 3), but does not establish a role in morphogenesis of the postsynaptic density itself. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It is well established that focal lesions such as those in the brainstem result in axonal loss, and that cortical demyelination, which occurs independently of white matter lesions, is associated with selective neuronal loss18; both these degenerative features are prominent determinants of progression18,19.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Severity locus impacts CNS tissue injury
What the sources say
- Partly supportedcites [18] Schirmer, L. et al. Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature 573, 75–82 (2019). sourceExperimental — accuracy not yet measured
The Abstract links focal plaques with progressive white-matter axonal damage, and the Results report selective loss of CUX2-expressing neurons in demyelinated cortical lesions (page numbers unavailable). The copy does not establish the brainstem-specific example, that cortical demyelination occurs independently of white-matter lesions, or that both degenerative features are prominent determinants of progression. (LLM, conf=0.84)
- Partly supportedcites [19] Absinta, M., Lassmann, H. & Trapp, B. D. Mechanisms underlying progression in multiple sclerosis. Curr. Opin. Neurol. 33, 277–285 (2020). sourceExperimental — accuracy not yet measured
The Neuropathology of progressive MS section (page unavailable) says subpial cortical demyelination can develop independently of white-matter lesions and identifies cortical lesions as a major substrate of disability. The Final pathways section (page unavailable) reports significant cortical neuronal loss, but says neuronal loss was not correlated with cortical demyelination in the myelocortical patients discussed. It describes axonal injury in white matter, not specifically brainstem lesions, and does not establish the claimed association with selective neuronal loss. (LLM, conf=0.85)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The intergenic MS severity variant rs10191329 is nearest to DYSF (3,692 base pairs to the transcription start site), and this gene was prioritized by the combined SNP-to-gene (cS2G)20 strategy based on enhancer-gene linking.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Gene prioritization and related traits
What the sources say
- Supportedcites [20] Gazal, S. et al. Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity. Nat. Genet. 54, 827–836 (2022). source
The citation is attached to the name of the cS2G strategy. In “Combining S2G strategies” (page unavailable), the paper describes constructing cS2G and lists EpiMap enhancer-gene linking among its constituent strategies. It identifies the method cited here; the variant-specific DYSF finding is the citing paper’s application of that method. (LLM, conf=0.89)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Genetic determinants of education may partly operate through indirect familial influences and socioeconomic factors34.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Supportedcites [34] Okbay, A. et al. Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals. Nat. Genet. 54, 437–449 (2022). source
In Results > Within-Family Analyses, the paper explains that the population effect of an educational-attainment polygenic index includes indirect effects from relatives, including genetic influences on parents’ education, socioeconomic status, and behavior. This supports the claim’s qualified wording that genetic determinants may partly operate through familial and socioeconomic pathways. (LLM, conf=0.92)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Similar protective effects of education have been observed in Alzheimer’s disease and frontotemporal dementia50,51, indicating some commonality with other neurodegenerative conditions.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Supportedcites [50] Gazzina, S. et al. Education modulates brain maintenance in presymptomatic frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry 90, 1124–1130 (2019). source
The Introduction states that educational attainment contributes to resilience against brain damage in neurodegenerative disorders including Alzheimer’s disease and FTD. The Neurodegeneration discussion reports reduced grey matter loss among more educated presymptomatic FTD subjects and describes the finding as consistent with previous longitudinal studies in Alzheimer’s disease. (LLM, conf=0.91)
- Partly supportedcites [51] Cabeza, R. et al. Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing. Nat. Rev. Neurosci. 19, 701–710 (2018). sourceExperimental — accuracy not yet measured
The Reserve section (page unavailable) describes education as promoting reserve that attenuates cognitive decline, and the paper discusses reserve in relation to Alzheimer’s disease. It does not report protective effects of education in frontotemporal dementia, so it does not support that part of the claim. (LLM, conf=0.82)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Furthermore, a few observational studies have documented an inverse association between educational attainment and subsequent MS disability31 as well as retinal neurodegeneration49.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Supportedcites [31] D’hooghe, M. B., Haentjens, P., Van Remoortel, A., De Keyser, J. & Nagels, G. Self-reported levels of education and disability progression in multiple sclerosis. Acta Neurol. Scand. 134, 414–419 (2016). source
The Discussion says an inverse relationship between education and disability has been reported on several occasions. The Cox proportional hazards analysis also finds a lower hazard of reaching the EDSS 6 disability milestone among respondents with relapsing-onset MS who reported more than 12 years of education. The paper reports a different pattern for progressive-onset MS, so the association should not be read as applying to every MS subtype. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Furthermore, a few observational studies have documented an inverse association between educational attainment and subsequent MS disability31 as well as retinal neurodegeneration49.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Supportedcites [49] Vasileiou, E. S. et al. Socioeconomic disparity is associated with faster retinal neurodegeneration in multiple sclerosis. Brain 144, 3664–3673 (2021). source
The Results section, “Socioeconomic status indicators and GCIPL atrophy in patients with multiple sclerosis” (page unavailable), reports that participants with the least education had faster retinal GCIPL atrophy than those with the most education. This supports the claimed inverse association in people with multiple sclerosis. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“We caution that neurocognitive reserve is a complex construct that is operationalized using proxies such as education, but it cannot be directly measured51.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Supportedcites [51] Cabeza, R. et al. Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing. Nat. Rev. Neurosci. 19, 701–710 (2018). source
The Reserve section says reserve cannot be measured directly and that studies use proxies, including education. It also describes different aspects of reserve that require different approaches to measurement. No page number is supplied in our copy. (LLM, conf=0.93)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“ZNF638 encodes the DNA-binding zinc finger protein 638, which mediates transcriptional repression of unintegrated retroviral DNA through recruitment of the human silencing hub (HUSH) complex and the histone methyltransferase SETDB123.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Supportedcites [23] Zhu, Y., Wang, G. Z., Cingöz, O. & Goff, S. P. NP220 mediates silencing of unintegrated retroviral DNA. Nature 564, 278–282 (2018). source
The screen description identifies NP220 as ZNF638, and the Abstract describes NP220 as a DNA-binding protein required for silencing unintegrated retroviral DNA. The ChIP description says NP220 brings HUSH and SETDB1 to that DNA; Extended Data Fig. 8 depicts the same mechanism for MLV. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“These findings would be consistent with education promoting neurocognitive reserve51, increasing resilience to neuronal degeneration resulting from MS injury and aging.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Supportedcites [51] Cabeza, R. et al. Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing. Nat. Rev. Neurosci. 19, 701–710 (2018). source
The Reserve section identifies education as a factor that promotes reserve and says it can attenuate age-related cognitive decline. The citation is attached specifically to the claim that education promotes neurocognitive reserve; the sentence’s application to MS injury is the citing authors’ interpretation. (LLM, conf=0.90)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Interestingly, the paralog dynamin-2 participates in membrane repair by wound-induced endocytosis in skeletal muscle45, which may point to a convergence of mechanisms with DYSF.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Partly supportedcites [45] McDade, J. R., Naylor, M. T. & Michele, D. E. Sarcolemma wounding activates dynamin-dependent endocytosis in striated muscle. FEBS J. 288, 160–174 (2021). sourceExperimental — accuracy not yet measured
The Introduction reports that wounding stimulates dynamin-dependent endocytosis in adult skeletal muscle fibers and identifies dynamin-2 as an isoform highly expressed in that muscle. But the Discussion says it remains unclear whether wound-induced endocytosis contributes to membrane resealing or is a detrimental consequence of wounding. The claim presents participation in repair as established when the paper describes it as a potential role. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Several exogenous and endogenous viruses have been considered in MS pathogenesis, with the most compelling evidence implicating respectively Epstein-Barr virus (EBV)40 and human endogenous retrovirus type-W (HERV-W)41.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Supportedcites [40] Bjornevik, K., Münz, C., Cohen, J. I. & Ascherio, A. Epstein–Barr virus as a leading cause of multiple sclerosis: mechanisms and implications. Nat. Rev. Neurol. 19, 160–171 (2023). source
Citation 40 is attached to EBV, not HERV-W. The Introduction says numerous viruses have been implicated in MS and describes strong, consistent evidence for EBV; the Temporal association section reports that only responses to EBV antigens were enriched in people who later developed MS. This supports the portion of the sentence attributed to this source. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [41] Kremer, D. et al. Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation. Ann. Neurol. 74, 721–732 (2013). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“As SNP-heritability can be sensitive to LD and allele frequency assumptions63, we also fitted a model with ten GRMs (GREML-LDMS) constructed from variants assigned to five MAF bins (0.01–0.1, 0.1–0.2, 0.2–0.3, 0.3–0.4 and 0.4–0.5) each divided into two by the median LD score in each bin.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > METHODS > Heritability estimation.
What the sources say
- Supportedcites [63] Evans, L. M. et al. Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits. Nat. Genet. 50, 737–745 (2018). source
The Discussion says single-component heritability estimates are highly sensitive to assumptions and that partitioning SNPs across LD and MAF bins provides more robust estimates. This supports the rationale attributed to the source. The citing authors’ choice to fit ten GRMs is their own method, not a result attributed to this paper. (LLM, conf=0.92)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“the protein has been found to accumulate in Aβ-containing extracellular neuritic plaques, in proportion to Alzheimer’s disease severity44.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Supportedcites [44] Galvin, J. E., Palamand, D., Strider, J., Milone, M. & Pestronk, A. The muscle protein dysferlin accumulates in the Alzheimer brain. Acta Neuropathol. 112, 665–671 (2006). source
The Results section (“Dysferlin in the AD brain”) localizes dysferlin accumulation to Aβ neuritic plaques. The Discussion says dysferlin accumulates in dystrophic neurites from mild dementia onward, with greater accumulation in more advanced disease. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The same chromatin repressors are involved in epigenetic silencing of endogenous retroviruses39.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Partly supportedcites [39] Robbez-Masson, L. et al. The HUSH complex cooperates with TRIM28 to repress young retrotransposons and new genes. Genome Res. 28, 836–845 (2018). sourceExperimental — accuracy not yet measured
The Discussion (Figure 7 model; page unavailable) says TRIM28 is required to repress endogenous retroviruses, and FAM208A also binds to them. It explicitly says FAM208A is not required for their repression, so the paper does not support the claim that both repressors silence endogenous retroviruses. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“in line with strong observational evidence of faster disability progression in smokers that reverses following cessation48.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Supportedcites [48] Manouchehrinia, A. et al. Tobacco smoking and disability progression in multiple sclerosis: United Kingdom cohort study. Brain 136, 2298–2304 (2013). source
The Discussion reports faster disability progression among ever-smokers and a significantly lower risk of reaching disability milestones among ex-smokers than current smokers. The Abstract adds that ex-smokers did not differ significantly from never-smokers in time to those milestones, supporting the claim that the faster progression associated with smoking reverses following cessation. (LLM, conf=0.88)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“The gene is highly expressed in the brain, particularly in oligodendrocytes and their precursor cells, and has been implicated in large-scale genetic studies of intelligence and general cognitive ability43.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Could not verifycites [43] Savage, J. E. et al. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nat. Genet. 50, 912–919 (2018). sourceExperimental — accuracy not yet measured
The Letters report brain-expression and intelligence associations for groups of genes, but the passages found do not identify ZNF638 among them. A figure label lists oligodendrocytes and their precursors without linking either cell type to ZNF638. Searches for ZNF638 and its claimed cell-specific expression found no passage addressing the gene-specific claim. (LLM, conf=0.72)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“The variants included were examined for instrument strength79 (mean F-statistic > 10; Supplementary Table 18).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > METHODS > Mendelian randomization.
What the sources say
- Supportedcites [79] Bowden, J. et al. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int. J. Epidemiol. 48, 728–742 (2019). source
The Methods section uses mean F-statistic to characterize instrument strength, describing low mean F-statistics as indicating weak instruments. The cited paper supports the strength-assessment method; the citing study’s observed value above 10 is attributed to its own Supplementary Table 18, not to this source. No page number is available in our copy. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, rs10191329 showed correlation (r2 > 0.6) with fine-mapped expression QTLs for the upstream gene ZNF638 (Supplementary Table 14) and weaker correlation with splicing QTLs for the same gene in brain (r2 0.3 to 0.4).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Gene prioritization and related traits
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PGS analysis of lifetime smoking index (β = 0.022 per standard deviation score increase, P = 0.004) and education also indicated consistent and independent associations with MS severity (Fig. 5b–c, Supplementary Tables 20 and 21, Methods).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Education, smoking modulate MS severity
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both these genes are highly expressed in neuronal and glial cells in the CNS with shared specificity for oligodendrocytes (Extended Data Fig. 5 and 6)”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Gene prioritization and related traits
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MR analyses did not indicate a causal role for either 25OHD levels or BMI in MS severity (Fig. 5a).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Education, smoking modulate MS severity
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The suggestive variant rs149097173 is intronic to DNM3 and PIGC, the latter also being nominated by cS2G.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Gene prioritization and related traits
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with estimates from our longitudinal analysis, homozygous risk allele carriers had experienced a 4-year shorter median time to EDSS 6.0, although differences were not significant in this smaller cohort (Supplementary Table 11).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Severity locus impacts CNS tissue injury
plaincorrelationaln = 290- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among other traits, rs10191329A has been inversely associated with intelligence, whereas for rs149097173 association is limited to height (Supplementary Tables 15 and 16).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Gene prioritization and related traits
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Variant rs149097173 is also intronic to PIGC, mutations in which can lead to intellectual disability and epilepsy25.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The first two principal components respectively captured the north-to-south and east-to-west gradients of European genetic structure.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > Extended Data
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“DYSF, ZNF638, DNM3 and PIGC are expressed in the brain.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > Extended Data
What the sources say
- Not matchedcites GTEx73
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“US and Canadian participants overlapped with those from other countries.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Based on self-reported ancestry, East European and Ashkenazi Jewish individuals constituted the majority of the predominantly US subcluster located at the bottom right of the discovery population (a).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“PIGC initiates biosynthesis of the glycosylphosphatidylinositol anchor25 (Extended Data Fig. 7).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Gene prioritization and related traits
What the sources say
- Not checked — no full text of the sourcecites [25] Edvardson, S. et al. Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability. J. Med. Genet. 54, 196–201 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both severity variants had a clinically meaningful impact on time to needing a walking aid, with the median interval from onset shortened by 3.7 years for homozygous risk allele carriers of the DYSF-ZNF638 variant (rs10191329) and 3.3 years for risk allele carriers of the DNM3-PIGC variant (rs149097173).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these results demonstrate a detrimental effect of smoking in people with MS and implicate educational attainment as a potential protective factor.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Education, smoking modulate MS severity
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“linkage disequilibrium (LD) score regression (LDSC) yielded an intercept not significantly different from 1 (1.006, 95% confidence interval [CI] 0.993 to 1.019), consistent with polygenicity driving inflation.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Discovery of an MS severity locus
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MR analyses also provide evidence for smoking and educational attainment as potential modifiable risk factors for MS progression.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The lead variant and an additional suggestive association replicated and showed concordant effects in a range of MS-specific longitudinal outcomes across tens of thousands of patient visits, likely reflecting progressive mechanisms (Supplementary Note).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
hedgedcorrelationaln = 22,000- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This pattern faithfully recapitulates the immune-related nature of susceptibility associations, further highlighting the striking difference from the heritability pattern observed for disease severity.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > RESULTS > Heritability and tissue enrichment
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Educational attainment and smoking are complex traits influenced by both genetic and environmental factors, and genetic predisposition may not have the same biological consequences as environmental changes (through policy), such that the predicted effect may not be realized.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We have identified genetic drivers of disability in MS, providing new directions for functional characterization and drug development targeted on the neurodegenerative component of the disease.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Although widely expressed, its functions are mainly characterized in skeletal muscle where it participates in calcium-mediated membrane repair and regeneration22.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [22] Bansal, D. et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168–172 (2003). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the MR sensitivity analyses did not find evidence of horizontal pleiotropy, it can only be tested indirectly and violation of this instrumental variable assumption cannot be entirely excluded.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- The authors state this as an assumption: The instrumental variable assumption of no horizontal pleiotropy holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We have not tested the robustness of these findings to alternative measures of educational attainment (e.g., on a continuous scale) or additional proxies of neurocognitive reserve.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Disease modifying therapy was not included as it is not a confounder (i.e. does not influence genotype) and may instead introduce collider bias57.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > METHODS > GWAS and replication.
What the sources say
- Not checked — no full text of the sourcecites [57] Aschard, H., Vilhjálmsson, B. J., Joshi, A. D., Price, A. L. & Kraft, P. Adjusting for heritable covariates can bias effect estimates in genome-wide association studies. Am. J. Hum. Genet. 96, 329–339 (2015). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Recessive pathogenic variants lead to muscular dystrophies (OMIM 254130, 253601, 606768).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Not matchedcites OMIM 254130, 253601, 606768
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our findings identify CNS resilience and reserve as likely determinants of MS progression, and may have broader implications for neurodegeneration.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Our observations are also in concordance with the proposed enhanced penetrance of monogenic causes of neurological disease reported to result from comorbidity with MS37,38.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [37] Kellar-Wood, H., Robertson, N., Govan, G. G., Compston, D. A. & Harding, A. E. Leber’s hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis. Ann. Neurol. 36, 109–112 (1994). source
- Not checked — no full text of the sourcecites [38] Ismail, A. et al. Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of C9ORF72. J. Neurol. Neurosurg. Psychiatry 84, 79–87 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Despite its widespread use and regulatory precedent, the EDSS has several shortcomings including its non-linear ordinal nature, variability between raters, overemphasis on ambulation, and inadequate capture of cognitive impairment52.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [52] Cohen, J. A., Reingold, S. C., Polman, C. H., Wolinsky, J. S. & International Advisory Committee on Clinical Trials in Multiple Sclerosis. Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects. Lancet Neurol. 11, 467–476 (2012). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In the survival analyses, events could only be observed at clinic visits and not in real-time.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Also, collider bias may occur when considering risk factors affecting both disease onset and progression.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“Variant rs149097173 is also intronic to PIGC, mutations in which can lead to intellectual disability and epilepsy25.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [25] Edvardson, S. et al. Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability. J. Med. Genet. 54, 196–201 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This may bias survival time estimates from clinical settings where follow-up intervals can vary.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Pathological characterization was undertaken blind to genotype status.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > METHODS > MS autopsy cohort and associations with neuropathology.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The proportional hazards assumption was examined by inspection of scaled Schoenfeld residuals.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > METHODS > Analysis of longitudinal outcomes.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“P values < 0.0083 were considered significant following Bonferroni correction for the number of variants and outcomes tested.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > METHODS > Analysis of longitudinal outcomes.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“P values less than 0.025 were considered significant (adjusting for two pathological variables).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > METHODS > MS autopsy cohort and associations with neuropathology.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We applied FDR correction for multiple testing within each enrichment analysis, and FDR-corrected P < 0.05 were considered statistically significant.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > METHODS > Heritability enrichment analyses.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper relies on this without support.
The independent MS autopsy cohort is representative of the broader MS population for assessing the effect of rs10191329 on CNS pathology.
“we examined the variant’s association with disease-relevant markers of tissue injury in an independent MS autopsy cohort comprising 4,652 tissue blocks in 290 individuals.”
The paper relies on this without support.
The ARMSS score is comparable across the discovery and replication cohorts.
“individual EDSS measures were converted to the age-related MS severity (ARMSS) score by ranking disability within age-specific strata13 (Methods).”
“Replication of variant associations was tested in existing data from nine independent cohorts totaling 9,805 cases”
The authors state this as an assumption.
The MR analysis assumes linearity and may not be applicable to individuals at the extremes of trait distributions, including for vitamin D and BMI.
“The MR analysis assumes linearity and may not be applicable to individuals at the extremes of trait distributions, including for vitamin D and BMI.”
The authors state this as an assumption.
The instrumental variable assumption of no horizontal pleiotropy holds.
“Although the MR sensitivity analyses did not find evidence of horizontal pleiotropy, it can only be tested indirectly and violation of this instrumental variable assumption cannot be entirely excluded.”
The authors state this as an assumption.
There is no sample overlap between the MS severity GWAS and the exposure GWAS, and no shared population stratification.
“Since we expect no sample overlap with our within-case GWAS, the LDSC intercept was constrained on the assumption of no shared population stratification.”
The authors state this as an assumption.
The three longitudinal disability outcomes are not expected to be independent.
“although the latter are not expected to be independent”
Statistics recomputed
Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.
- Consistentz = 3.1reported p = .002 · recomputed p = .002
“(Z = 3.1, p = .002”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > Extended Data
“HR and two-sided P values were obtained from Cox proportional hazards models using imputed allele dosage (b–c; Methods).”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > METHODS > Analysis of longitudinal outcomes.
“Hazard ratios were calculated using dosages for rs10191329 and carrier status for rs149097173 given its low frequency.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > Extended Data
“PIGC expression in brain neuronal and glial cells, missing here, is demonstrated in Extended Data Fig. 8.”
§ Novel genetic locus and CNS resilience modulate multiple sclerosis severity > Extended Data
“Figure: Extended Data Fig. 8 | Genetic correlations with MS severity.”
Citations
Cites
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Cited by
Sorted by citations
Items 201–247 of 247
Genetically reduced MTHFR activity confers protection against multiple sclerosis
Daghlas, I., Pluvinage, J. V., & Gill, D. (2025) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2025.578784
Кулакова, О. Г., Kozin, M. S., Сергеевич, К. И., Favorova, O. O., & Boyko, A. N. (2025) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro2025125101121
Sulcebe, G., Shyti, E., Kurti-Prifti, M., Kasemi, D., Deda, A., Mikerezi, I., Nezaj, R., Verlaku, A., Likaj, S., & Kruja, J. (2025) · medRxiv · doi:10.64898/2025.12.01.25341397
Winschel, I., Willing, A., Engler, J. B., Walkenhorst, M., Meurs, N., Binkle-Ladisch, L., Woo, M. S., Pfeffer, L. K., Sonner, J. K., Borgmeyer, U., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26721237
Winschel, I., Willing, A., Engler, J. B., Walkenhorst, M., Meurs, N., Binkle-Ladisch, L., Woo, M. S., Pfeffer, L. K., Sonner, J. K., Borgmeyer, U., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26721240
Winschel, I., Willing, A., Engler, J. B., Walkenhorst, M., Meurs, N., Binkle-Ladisch, L., Woo, M. S., Pfeffer, L. K., Sonner, J. K., Borgmeyer, U., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26721243
Winschel, I., Willing, A., Engler, J. B., Walkenhorst, M., Meurs, N., Binkle-Ladisch, L., Woo, M. S., Pfeffer, L. K., Sonner, J. K., Borgmeyer, U., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26721246
Winschel, I., Willing, A., Engler, J. B., Walkenhorst, M., Meurs, N., Binkle-Ladisch, L., Woo, M. S., Pfeffer, L. K., Sonner, J. K., Borgmeyer, U., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26721234
New Horizons for Multiple Sclerosis Therapy: 2025 and Beyond
Birnbaum, G. (2025) · Annals of Neurology · doi:10.1002/ana.78121
Brain Atrophy Associated With Risk Variant rs10191329 Extends Beyond Multiple Sclerosis
Corsten, C. E. A., Marques, A. M., Vinke, E. J., de Mol, C. L., Neuteboom, R. F., Ikram, M. K., Ghanbari, M., Wolters, F. J., Wokke, B. H. A., Vernooij, M. W., et al. (2026) · Annals of Neurology · doi:10.1002/ana.78148 · Cited by 1
Self-citationImmunotherapies in progressive multiple sclerosis
Neziraj, T., Kappos, L., & Pröbstel, A. (2026) · Handbook of clinical neurology · doi:10.1016/b978-0-323-90887-0.00021-3 · Cited by 2
Fisiopatologia della sclerosi multipla
Dubessy, A., & Stankoff, B. (2026) · EMC - Neurologia · doi:10.1016/s1634-7072(25)51364-8
Zhou, X., Zhang, Y., Sun, L., Kwok, C. K., & Zhang, J. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.20.700564
“Besides transcripts of DDX5, TNRC6B, and RAB11A, which are captured as CIRBP protein targets in OPCs, the ZNF638 RNA, which is responsible for repairing in multiple sclerosis, was found to be involved in chromatin remodeling 36 .”
Corsten, C. E. A., Marques, A. M., van Hasselt, Y., van Rooij, J., Smets, I., van Luijn, M. M., Neuteboom, R. F., Wokke, B. H. A., & Smolders, J. (2026) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2026.107101
Self-citationCalvo‐Barreiro, L., Boutitah-Benyaich, I., Eixarch, H., Espejo, C., & Gabr, M. T. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03768-5
“While certain human leukocyte antigen (HLA) and non-HLA genes contribute to susceptibility [4–7], environmental factors such as viral infections, smoking, and vitamin D deficiency also play critical roles [8, 9].”
The genetics of multiple sclerosis: an updated perspective
Bellucci, G., & Baranzini, S. E. (2026) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001478
Self-citationThe genetic architecture of multiple sclerosis in 2026: From susceptibility to disease progression
Bourguiba, S., Paris, J., Gourraud, P., & Vince, N. (2026) · Revue Neurologique · doi:10.1016/j.neurol.2026.03.006
Contrasting genetic architectures of multiple sclerosis susceptibility and outcome phenotypes
Sorella, M. Y., Ding, Y., Garcia, A. M., Ygonia, M., Wang, L., Jacobs, B. M., & Harroud, A. (2026) · Revue Neurologique · doi:10.1016/j.neurol.2026.03.007 · Cited by 1
Self-citationMultiple sclerosis severity: integrative insights into genetic and nongenetic risk factors
Almramhi, M. M. (2026) · The Egyptian Journal of Neurology Psychiatry and Neurosurgery · doi:10.1186/s41983-026-01164-7
Ensemble Approaches to Screening, Diagnosis, and Subtyping of Multiple SclerosisPreprint
Yang, I. Y., Patil, A., Jin, O. Y., Loud, S., Buxhoeveden, S., & Zhang, D. Y. (2026) · medRxiv · doi:10.64898/2026.04.19.26351230
Rethinking prognosis in multiple sclerosis: a multiaxial perspective
Prosperini, L., Tortorella, C., Barkhof, F., Battistini, L., Bodini, B., Calabrese, M., Chard, D., Ciccarelli, O., Stefano, N. D., Enzinger, C., et al. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-026-01212-z
Self-citationGenetic‐Proteomic Integration Identifies Predictive Plasma Proteins for Multiple Sclerosis
Ding, Y., Hamitouche, D., Thebault, S., Kearns, P., Abdelhak, A., & Harroud, A. (2026) · Annals of Neurology · doi:10.1002/ana.78256
Self-citationSomatic variation in multiple sclerosis: from blood to brain
Rubio, J. P. (2026) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2026.102488
Self-citationDCIR-mediated inhibitory regulation of TLR7-MyD88 axis prevents autoimmune neuroinflammation
Fujioka, A., Shimizu, K., Nakayama, S., Ueno, D., Chiba, Y., Nakashima, I., Fujimori, J., Shirota, Y., Iwakura, Y., Muraki, Y., et al. (2026) · iScience · doi:10.1016/j.isci.2026.116094
Noroozi, R., Tejera, C. H., Chen, M. Z., et al. (2026) · medRxiv · doi:10.64898/2026.05.27.26354239
Self-citationJiang, Y., Xiao, J., Kockum, I. S., Stridh, P., Liu, Q., Olsson, T. P., Alfredsson, L. S., & Jiang, X. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03895-z
Self-citationEpigenetic and genetic insights for tailored therapeutic strategies in multiple sclerosis
Mariki, A., Mousavi, S. M., Kohlmeier, K. A., Kamali, H., & Shabani, M. (2026) · Personalized Medicine · doi:10.1080/17410541.2026.2678216
Lütje, L., Chen, J. Q. A., Hamann, J., Smolders, J., Huitinga, I., & van den Bosch, A. M. R. (2026) · Acta Neuropathologica · doi:10.1007/s00401-026-03040-3
Self-citationKhayat-Khoei, M., Houtchens, M. K., & Khoury, S. J. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-45863-7.00078-0
Guo, M., Liu, H., & Han, J. (2026) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2026.126078
Krantz, B. A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.30.735650 · Cited by 2
Polygenic risk scores in neurological disorders: restless legs syndrome as a translational model
Winkelmann, J., & Schormair, B. (2026) · Medizinische Genetik · doi:10.1515/medgen-2026-3015
Chen, K., Zou, Q., & Yao, Y. (2026) · Genes · doi:10.3390/genes17070810
“We analyzed two primary outcomes: (1) MS susceptibility using summary statistics from the largest European-ancestry GWAS (47,429 cases; 68,374 controls) [7], and (2) disease severity using age-related MS severity (ARMSS) scores ( N = 12,584) [8].”
Targeting progressive multiple sclerosis: Toward mechanism‐informed precision medicine
Piehl, F., Castelo‐Branco, G., Jagodic, M., & Olsson, T. P. (2026) · Journal of Internal Medicine · doi:10.1111/joim.70125 · Cited by 1
Self-citationSatyanarayan, S., & LUBLIN, F. D. (2026) · Multiple Sclerosis Journal · doi:10.1177/13524585261471767
Tripathi, T., Gospodarska, E., Geran, R., Sperber, P. S., Schmitz‐Hübsch, T., Paul, F., & Carlberg, C. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1845005 · Cited by 1
Elhelaly, M., El-Hanafy, D. A., Shaker, O. G., et al. (2026) · Egyptian Journal of Basic and Applied Sciences · doi:10.1080/2314808x.2026.2711176
Tsai, H., Piya, S., Wang, J., Zhu, J., Hu, W., Gehrke, A. R., Cao, S., Guise, A. J., Chan, S. J., Sheehan, M. J., et al. (2026) · Frontiers in Bioinformatics · doi:10.3389/fbinf.2026.1832826 · Cited by 2
“A recent GWAS revealed a locus associated with MS progression (International Multiple Sclerosis Genetics Consortium MultipleMS Consortium, 2023).”
Genetic subtypes of multiple sclerosis severity are uncoupled from inflammatory lesion burden
Abbadessa, G., Kreft, K. L., Howell, O. W., de Oliveira, J. V. C., Cooze, B., Papadaki, A., Jacinto, J. M., Farkas, I., Leung, Y.-Y., Bonavita, S., et al. (2026) · Acta Neuropathologica · doi:10.1007/s00401-026-03062-x
Self-citationBinMowyna, M. N., Alhenaky, A., Khalifa, N. E., Noredin, A., & Batool, U. (2026) · 3 Biotech · doi:10.1007/s13205-026-05018-0
Han, Y., Zheleznyakova, G. Y., Liang, H., Sorini, C., Kakhki, M. P., Ruffin, N., Hallen, N., Prakash, C. R., Beckers, V., Ivanova, E., et al. (2026) · EBioMedicine · doi:10.1016/j.ebiom.2026.106454
Self-citationFujimoto, R., Ogawa, K., Namba, S., Ogawa, Y., Edahiro, R., Sonehara, K., Tagawa, S., Watanabe, M., Yata, T., Shirai, Y., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02741-5
“Previous MS GWAS results have prioritized cell types in which MS risk variants exhibit functional roles and have highlighted the importance of peripheral immune cells, including T cells, B cells and microglia (that is, immune cells specifically found in the CNS) 10,16 .”
Self-citationCalabrese, M., Magliozzi, R., Tamanti, A., Ziccardi, S., Eccher, C., Biasi, P., Pizzini, F. B., & Marastoni, D. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-026-01263-2
Genetic modification of obesity-associated disability progression in multiple sclerosis
Guo, J., Wu, J., Olsson, T. P., Alfredsson, L. S., & Hedström, A. K. (2026) · Journal of Neurology · doi:10.1007/s00415-026-14091-7 · Cited by 1
Self-citationBalshi, A., Dobson, R., Houtchens, M. K., McConville, K., McElrath, T. F., Sadovnick, A. D., Tesfalul, M. A., Hellwig, K., & Bove, R. M. (2026) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2026.08.043
Association Between Genetic Ancestry and Multiple Sclerosis Severity
Jacobs, B. M., Tregaskis-Daniels, E., Schalk, L., et al. (2026) · Annals of Neurology · doi:10.1002/ana.78350
Self-citationFamily history of multiple sclerosis and long-term outcomes
Hedström, A. K., Olsson, T., & Alfredsson, L. S. (2026) · Journal of Neurology · doi:10.1007/s00415-026-14162-9
Self-citation
Metadata
- Authors
- International Multiple Sclerosis Genetics Consortium, Harroud, A., Stridh, P., McCauley, J. L., Saarela, J., van den Bosch, A. M. R., Engelenburg, H. J., Beecham, A. H., Alfredsson, L., Alikhani, K., Amezcua, L., Andlauer, T. F. M., Ban, M., Barcellos, L. F., Barizzone, N., Berge, T., Berthele, A., Bittner, S., Bos, S. D., Briggs, F. B. S., Caillier, S. J., Calabresi, P. A., Caputo, D., Carmona-Burgos, D. X., Cavalla, P., Celius, E. G., Cerono, G., Chinea, A. R., Chitnis, T., Clarelli, F., Comabella, M., Comi, G., Cotsapas, C., Cree, B. C. A., D’Alfonso, S., Dardiotis, E., De Jager, P. L., Delgado, S. R., Dubois, B., Engel, S., Esposito, F., Fabis-Pedrini, M. J., Filippi, M., Fitzgerald, K. C., Gasperi, C., Gomez, L., Gomez, R., Hadjigeorgiou, G., Hamann, J., Held, F., Henry, R. G., Hillert, J., Huang, J., Huitinga, I., Islam, T., Isobe, N., Jagodic, M., Kermode, A. G., Khalil, M., Kilpatrick, T. J., Konidari, I., Kreft, K. L., Lechner-Scott, J., Leone, M., Luessi, F., Malhotra, S., Manouchehrinia, A., Manrique, C. P., Martinelli-Boneschi, F., Martinez, A. C., Martinez-Maldonado, V., Mascia, E., Metz, L. M., Midaglia, L., Montalban, X., Oksenberg, J. R., Olsson, T., Oturai, A., Pääkkönen, K., Parnell, G. P., Patsopoulos, N. A., Pericak-Vance, M. A., Piehl, F., Rubio, J. P., Santaniello, A., Santoro, S., Schaefer, C., Sellebjerg, F., Shams, H., Shchetynsky, K., Silva, C., Siokas, V., Søndergaard, H. B., Sorosina, M., Taylor, B., Vandebergh, M., Vasileiou, E. S., Vecchio, D., Voortman, M. M., Weiner, H. L., Wever, D., Yong, V. W., Hafler, D. A., Stewart, G. J., Compston, A., Zipp, F., Harbo, H. F., Hemmer, B., Goris, A., Smolders, J., Hauser, S. L., Kockum, I., Sawcer, S. J., Baranzini, S. E., MultipleMS Consortium, Harroud, A., Jónsdóttir, I., Blanco, Y., Llufriu, S., Madireddy, L., Saiz, A., Villoslada, P., & Stefánsson, K.
- Affiliations
- Karolinska University Hospital (SE)
- University of Miami (US)
- University of Helsinki (FI)
- Netherlands Institute for Neuroscience (NL)
- University of Calgary (CA)
- University of Southern California (US)
- Technical University of Munich (DE)
- University of Cambridge (GB)
- University of California, Berkeley (US)
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- Oslo University Hospital (NO)
- Johannes Gutenberg University Mainz (DE)
- Case Western Reserve University (US)
- University of California, San Francisco (US)
- Johns Hopkins University (US)
- Don Carlo Gnocchi Foundation (IT)
- University of Turin (IT)
- Brigham and Women's Hospital (US)
- IRCCS Ospedale San Raffaele (IT)
- Vall d'Hebron Institut de Recerca (ES)
- Broad Institute (US)
- University of Thessaly (GR)
- Universitair Ziekenhuis Leuven (BE)
- Vita-Salute San Raffaele University (IT)
- University of Cyprus (CY)
- Kyushu University (JP)
- Murdoch University (AU)
- Medical University of Graz (AT)
- The Royal Melbourne Hospital (AU)
- Erasmus MC (NL)
- Casa Sollievo della Sofferenza (IT)
- Copenhagen University Hospital (DK)
- The University of Sydney (AU)
- The University of Melbourne (AU)
- Kaiser Permanente (US)
- University of Copenhagen (DK)
- University of Tasmania (AU)
- KU Leuven (BE)
- Munich Cluster for Systems Neurology (DE)
- deCODE Genetics (Iceland) (IS)
- Hospital Clínic de Barcelona (ES)
- Corresponding author
- Sawcer, Stephen J.
- Baranzini, Sergio E.
- ORCID
- Stridh, Pernilla
- McCauley, Jacob L.
- Saarela, Janna
- Engelenburg, Hendrik J.
- Beecham, Ashley H.
- Alfredsson, Lars
- Alikhani, Katayoun
- Amezcua, Lilyana
- Andlauer, Till F. M.
- Ban, Maria
- Barcellos, Lisa F.
- Barizzone, Nadia
- Berge, Tone
- Berthele, Achim
- Bittner, Stefan
- Bos, Steffan D.
- Briggs, Farren B. S.
- Caillier, Stacy J.
- Calabresi, Peter A.
- Caputo, Domenico
- Carmona-Burgos, David X.
- Cavalla, Paola
- Celius, Elisabeth G.
- Cerono, Gabriel
- Chinea, Angel R.
- Chitnis, Tanuja
- Clarelli, Ferdinando
- Comabella, Manuel
- Cotsapas, Chris
- Cree, Bruce C. A.
- D’Alfonso, Sandra
- Dardiotis, Efthimios
- Delgado, Silvia R.
- Dubois, Bénédicte
- Engel, Sinah
- Esposito, Federica
- Filippi, Massimo
- Fitzgerald, Kathryn C.
- Gasperi, Christiane
- Gomez, Refujia
- Hadjigeorgiou, Georgios
- Hamann, Jörg
- Held, Friederike
- Henry, Roland G.
- Hillert, Jan
- Huang, Jesse
- Huitinga, Inge
- Islam, Talat
- Isobe, Noriko
- Jagodic, Maja
- Kermode, Allan G.
- Khalil, Michael
- Kilpatrick, Trevor J.
- Konidari, Ioanna
- Kreft, Karim L.
- Leone, Maurizio
- Luessi, Felix
- Malhotra, Sunny
- Manouchehrinia, Ali
- Mascia, Elisabetta
- Metz, Luanne M.
- Midaglia, Luciana
- Oksenberg, Jorge R.
- Olsson, Tomas
- Pääkkönen, Kimmo
- Parnell, Grant P.
- Patsopoulos, Nikolaos A.
- Piehl, Fredrik
- Rubio, Justin P.
- Santaniello, Adam
- Santoro, Silvia
- Schaefer, Catherine
- Sellebjerg, Finn
- Shams, Hengameh
- Shchetynsky, Klementy
- Siokas, Vasileios
- Søndergaard, Helle B.
- Sorosina, Melissa
- Taylor, Bruce
- Vandebergh, Marijne
- Vecchio, Domizia
- Voortman, Margarete M.
- Weiner, Howard L.
- Wever, Dennis
- Yong, V. Wee
- Hafler, David A.
- Compston, Alastair
- Zipp, Frauke
- Harbo, Hanne F.
- Hemmer, Bernhard
- Goris, An
- Smolders, Joost
- Hauser, Stephen L.
- Kockum, Ingrid
- Sawcer, Stephen J.
- Baranzini, Sergio E.
- Jónsdóttir, Ingileif
- Blanco, Yolanda
- Saiz, Albert
- Villoslada, Pablo
- Venue
- Nature
- Published
- 2023-06-28
- Volume
- 619
- Issue
- 7969
- Pages
- 323-331
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC10602210
- OpenAlex
- W4382394400
- Semantic Scholar
- 69e4ed42c45dbea6fe4d5c4bc9018e4a7b0c984f
- Cited by
- 243
- References
- 115
- Citations by year
- 2026: 62 · 2025: 69 · 2024: 81 · 2023: 30
- FWCI
- 40.76
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- PubMed Central (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion, cc-by)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Apollo (cc-by)
- Funders
- National Multiple Sclerosis Society (733161, RG‐1707‐28657, FAN-1808-32256, JF-1808-32223)
- Bristol-Myers Squibb Foundation
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Sanofi
- Yale University
- Biogen
- Kaiser Permanente
- Teva Pharmaceutical Industries
- Alexion Pharmaceuticals
- Celgene
- Helsingin Yliopisto
- Regeneron Pharmaceuticals
- TG Therapeutics
- Race to Erase MS
- International Progressive MS Alliance (PA-1604-08492)
- Disarm Therapeutics
- Multiple Sclerosis Society of Canada (FAN-1808-32256)
- National Institute for Health and Care Research
- Multiple Sclerosis Society (JF-1808-32223, RG-1707-28657, PA-1604-08492)
- European Commission (733161, HORIZON2020)
- University of Tasmania
- Deutsche Forschungsgemeinschaft (TR‐128, EXC 2145, EXC 2145SyNergy, 390857198, CRC TR-128)
- Bundesministerium für Bildung und Forschung
- Sun Yat-sen University
- Fonds Wetenschappelijk Onderzoek (FWO G.07334.15, G.07334.15, 11ZZZ21N)
- Ministero della Salute (RF-2016-02361294)
- KU Leuven (C24/16/045)
- Knut och Alice Wallenbergs Stiftelse
- Max-Planck-Gesellschaft
- Vetenskapsrådet (2020-01638)
- Università degli Studi del Piemonte Orientale (733161)
- Forskningsrådet om Hälsa, Arbetsliv och Välfärd
- Red Española de Esclerosis Múltiple (RD16/0015/0002,, RD16/0015/0003)
- Vlaamse regering
- Mitsubishi Tanabe Pharma Corporation
- Menzies Institute for Medical Research
- Idorsia Pharmaceuticals
- Multiple Sclerosis Society of Western Australia
- National Institutes of Health (RG-1707-28657, JF-1808-32223, R01ES017080, R01NS049510, R01AI076544, R01NS099240)
- Genentech
- EMD Serono
- University of California, San Francisco
- Sanofi Genzyme
- Novartis Institutes for BioMedical Research
- Instituto de Salud Carlos III (PI15/00587, PI18/01030, RD16/0015/0002, RD16/0015/0003)
- Erasmus Universitair Medisch Centrum Rotterdam
- NIHR Cambridge Biomedical Research Centre
- National Institute of Nursing Research (R01 NR017431)
- National Institute of Allergy and Infectious Diseases (R01AI076544)
- National Institute of Neurological Disorders and Stroke (R01 NS096212, R01 NS099240, R35 NS111644, R01 NS 049510)
- National Institute of Environmental Health Sciences (R01 ES017080)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- multiple sclerosis, disease progression, disease severity, neurodegeneration, educational attainment, brainstem pathology, cortical pathology, heritability enrichment
- MeSH terms
- Dysferlin, Aging, Brain, Brain Stem, DNA-Binding Proteins, Educational Status, Hexosyltransferases, Homozygote, Humans, Membrane Proteins, Multiple Sclerosis, Time Factors, Transcription Factors, Case-Control Studies, RNA-Binding Proteins, Disease Progression, Mobility Limitation, Genome-Wide Association Study, Young Adult, Cognitive Reserve, Protective Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-13, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-13 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
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