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Cited by 247Multiple Sclerosis Research StudiesGenetic Associations and EpidemiologyPsoriasis: Treatment and Pathogenesis

Locus for severity implicates CNS resilience in progression of multiple sclerosis

Open access
International Multiple Sclerosis Genetics Consortium, Harroud, Adil, Stridh, Pernilla, McCauley, Jacob L., Saarela, Janna, van den Bosch, Aletta M. R., Engelenburg, Hendrik J., Beecham, Ashley H. +115 more·2023·Nature
DOI 10.1038/s41586-023-06250-xPMC PMC10602210

Published version of a preprint

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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.

AI snapshot

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41586-023-06250-x

Cites

111 of 111 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

48 of 61 cited sources checked · 27 supported · 0 flagged · accuracy not yet measured

  • Interpretationreasoning

    An independent genetic architecture determines the clinical course of MS.

    “These findings, together with the concordance for outcome within families7, suggest that an independent genetic architecture determines the clinical course of the disease”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Chataway, J. et al. Multiple sclerosis in sibling pairs: an analysis of 250 families. J. Neurol. Neurosurg. Psychiatry 71, 757–761 (2001). source
  • Premisecitation

    MS susceptibility risk variants do not appear to have any impact on disease severity.

    “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.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [5] International Multiple Sclerosis Genetics Consortium. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011). source
    • cites [6] George, M. F. et al. Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies. Neurol. Genet. 2, e87 (2016). source

      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)

      Experimental — accuracy not yet measured
  • Findingcitation

    Repeating the heritability enrichment analysis for MS susceptibility revealed strong enrichment in lymphoid organs, immune lymphoid and myeloid cells, and tissues with immunological functions.

    “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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019). source
  • Interpretationown data

    These findings indicate a key role of CNS resilience and neurocognitive reserve in determining outcome in MS.

    “In contrast to immune-driven susceptibility3, these findings indicate a key role of CNS resilience and neurocognitive reserve in determining outcome in MS.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019). source
  • Findingown data

    Partitioned heritability analysis by functional annotation with 53 categories did not identify strong enrichment in any category after correction for multiple testing.

    “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.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Finucane, H. K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015). source
  • May combine two claims. 33
  • Classified as probably not a substantial claim. 38

  • May combine two claims.

    Premisecitation

    Published efforts to systematically interrogate MS severity have only involved modest numbers of cases and have not identified any convincingly associated genetic variants.

    “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.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [5] International Multiple Sclerosis Genetics Consortium. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011). source

      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)

      Experimental — accuracy not yet measured
    • cites [10] International Multiple Sclerosis Genetics Consortium. Genome-wide association study of severity in multiple sclerosis. Genes Immun. 12, 615–625 (2011). source
    • cites [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). source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Homozygous rs10191329 risk allele carriers demonstrated more severe MS-specific brainstem and cortical pathology, which result in axonal and neuronal degeneration respectively and drive progression.

    “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.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [18] Schirmer, L. et al. Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature 573, 75–82 (2019). source

      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)

      Experimental — accuracy not yet measured
    • cites [19] Absinta, M., Lassmann, H. & Trapp, B. D. Mechanisms underlying progression in multiple sclerosis. Curr. Opin. Neurol. 33, 277–285 (2020). source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Integrated analysis of genetically regulated and compound-perturbed gene expression revealed significant enrichment for CNS-acting compounds and identified chromatin remodeling via histone deacetylase inhibitors as a potential therapeutic strategy for slowing progression.

    “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”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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). source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DYSF is implicated in membrane repair; ZNF638 mediates the silencing of unintegrated viral DNA.

    “DYSF is implicated in membrane repair22; ZNF638 mediates the silencing of unintegrated viral DNA23.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [22] Bansal, D. et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168–172 (2003). source
    • cites [23] Zhu, Y., Wang, G. Z., Cingöz, O. & Goff, S. P. NP220 mediates silencing of unintegrated retroviral DNA. Nature 564, 278–282 (2018). source

  • May combine two claims.

    Premisecitation

    DNM3 participates in the morphogenesis of the postsynaptic density and excitatory synaptic transmission.

    “DNM3 participates in the morphogenesis of the postsynaptic density and excitatory synaptic transmission24”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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). source

      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)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Focal lesions such as those in the brainstem result in axonal loss, and cortical demyelination is associated with selective neuronal loss; both are prominent determinants of progression.

    “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.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [18] Schirmer, L. et al. Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature 573, 75–82 (2019). source

      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)

      Experimental — accuracy not yet measured
    • cites [19] Absinta, M., Lassmann, H. & Trapp, B. D. Mechanisms underlying progression in multiple sclerosis. Curr. Opin. Neurol. 33, 277–285 (2020). source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    The intergenic MS severity variant rs10191329 is nearest to DYSF (3,692 base pairs to the transcription start site), and DYSF was prioritized by the combined SNP-to-gene (cS2G) strategy based on enhancer-gene linking.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Genetic determinants of education may partly operate through indirect familial influences and socioeconomic factors.

    “Genetic determinants of education may partly operate through indirect familial influences and socioeconomic factors34.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Similar protective effects of education have been observed in Alzheimer's disease and frontotemporal dementia, indicating some commonality with other neurodegenerative conditions.

    “Similar protective effects of education have been observed in Alzheimer’s disease and frontotemporal dementia50,51, indicating some commonality with other neurodegenerative conditions.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [50] Gazzina, S. et al. Education modulates brain maintenance in presymptomatic frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry 90, 1124–1130 (2019). source
    • cites [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 (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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A few observational studies have documented an inverse association between educational attainment and subsequent MS disability.

    “Furthermore, a few observational studies have documented an inverse association between educational attainment and subsequent MS disability31 as well as retinal neurodegeneration49.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A few observational studies have documented an inverse association between educational attainment and retinal neurodegeneration.

    “Furthermore, a few observational studies have documented an inverse association between educational attainment and subsequent MS disability31 as well as retinal neurodegeneration49.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [49] Vasileiou, E. S. et al. Socioeconomic disparity is associated with faster retinal neurodegeneration in multiple sclerosis. Brain 144, 3664–3673 (2021). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Neurocognitive reserve is a complex construct that is operationalized using proxies such as education, but it cannot be directly measured.

    “We caution that neurocognitive reserve is a complex construct that is operationalized using proxies such as education, but it cannot be directly measured51.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [51] Cabeza, R. et al. Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing. Nat. Rev. Neurosci. 19, 701–710 (2018). source

  • Classified as probably not a substantial claim.

    Premisecitation

    ZNF638 encodes the DNA-binding zinc finger protein 638, which mediates transcriptional repression of unintegrated retroviral DNA through recruitment of the HUSH complex and SETDB1.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] Zhu, Y., Wang, G. Z., Cingöz, O. & Goff, S. P. NP220 mediates silencing of unintegrated retroviral DNA. Nature 564, 278–282 (2018). source

  • May combine two claims.

    Interpretationcitation

    These findings would be consistent with education promoting neurocognitive reserve, increasing resilience to neuronal degeneration resulting from MS injury and aging.

    “These findings would be consistent with education promoting neurocognitive reserve51, increasing resilience to neuronal degeneration resulting from MS injury and aging.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [51] Cabeza, R. et al. Maintenance, reserve and compensation: the cognitive neuroscience of healthy ageing. Nat. Rev. Neurosci. 19, 701–710 (2018). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Paralogue dynamin-2 participates in membrane repair by wound-induced endocytosis in skeletal muscle.

    “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.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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). source

      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)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Several exogenous and endogenous viruses have been considered in MS pathogenesis, with the most compelling evidence implicating EBV and HERV-W.

    “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.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [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
    • cites [41] Kremer, D. et al. Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation. Ann. Neurol. 74, 721–732 (2013). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    As SNP-heritability can be sensitive to LD and allele frequency assumptions, we also fitted a model with ten GRMs.

    “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.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DYSF protein accumulates in Aβ-containing extracellular neuritic plaques, in proportion to Alzheimer's disease severity.

    “the protein has been found to accumulate in Aβ-containing extracellular neuritic plaques, in proportion to Alzheimer’s disease severity44.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The same chromatin repressors are involved in epigenetic silencing of endogenous retroviruses.

    “The same chromatin repressors are involved in epigenetic silencing of endogenous retroviruses39.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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). source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Strong observational evidence shows faster disability progression in smokers that reverses following cessation.

    “in line with strong observational evidence of faster disability progression in smokers that reverses following cessation48.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Manouchehrinia, A. et al. Tobacco smoking and disability progression in multiple sclerosis: United Kingdom cohort study. Brain 136, 2298–2304 (2013). source

  • May combine two claims.

    Premisecitation

    ZNF638 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 ability.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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). source

      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)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The variants included were examined for instrument strength (mean F-statistic > 10).

    “The variants included were examined for instrument strength79 (mean F-statistic > 10; Supplementary Table 18).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Findingown data

    rs10191329 showed correlation (r2 > 0.6) with fine-mapped expression QTLs for ZNF638 and weaker correlation with splicing QTLs for the same gene in brain (r2 0.3 to 0.4).

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PGS analysis of lifetime smoking index (β = 0.022 per standard deviation score increase, P = 0.004) and education indicated consistent and independent associations with MS severity.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both DYSF and ZNF638 are highly expressed in neuronal and glial cells in the CNS with shared specificity for oligodendrocytes.

    “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)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MR analyses did not indicate a causal role for either 25OHD levels or BMI in MS severity.

    “MR analyses did not indicate a causal role for either 25OHD levels or BMI in MS severity (Fig. 5a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The suggestive variant rs149097173 is intronic to DNM3 and PIGC, the latter also being nominated by cS2G.

    “The suggestive variant rs149097173 is intronic to DNM3 and PIGC, the latter also being nominated by cS2G.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Homozygous risk allele carriers in an independent MS autopsy cohort had experienced a 4-year shorter median time to EDSS 6.0, although differences were not significant.

    “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).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    rs10191329A has been inversely associated with intelligence, whereas for rs149097173 association is limited to height.

    “Among other traits, rs10191329A has been inversely associated with intelligence, whereas for rs149097173 association is limited to height (Supplementary Tables 15 and 16).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    rs149097173 is also intronic to PIGC.

    “Variant rs149097173 is also intronic to PIGC, mutations in which can lead to intellectual disability and epilepsy25.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The first two principal components respectively captured the north-to-south and east-to-west gradients of European genetic structure.

    “The first two principal components respectively captured the north-to-south and east-to-west gradients of European genetic structure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    DYSF, ZNF638, DNM3 and PIGC are expressed in the brain.

    “DYSF, ZNF638, DNM3 and PIGC are expressed in the brain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites GTEx73

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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    US and Canadian participants overlapped with those from other countries.

    “US and Canadian participants overlapped with those from other countries.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    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.

    “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).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PIGC initiates biosynthesis of the glycosylphosphatidylinositol anchor.

    “PIGC initiates biosynthesis of the glycosylphosphatidylinositol anchor25 (Extended Data Fig. 7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Interpretationown data

    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 rs10191329 and 3.3 years for risk allele carriers of rs149097173.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These results demonstrate a detrimental effect of smoking in people with MS and implicate educational attainment as a potential protective factor.

    “Together, these results demonstrate a detrimental effect of smoking in people with MS and implicate educational attainment as a potential protective factor.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    LD score regression yielded an intercept not significantly different from 1 (1.006, 95% CI 0.993 to 1.019), consistent with polygenicity driving inflation.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    MR analyses provide evidence for smoking and educational attainment as potential modifiable risk factors for MS progression.

    “MR analyses also provide evidence for smoking and educational attainment as potential modifiable risk factors for MS progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    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.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The pattern of immune enrichment for susceptibility recapitulates the immune-related nature of susceptibility associations and highlights the difference from severity heritability.

    “This pattern faithfully recapitulates the immune-related nature of susceptibility associations, further highlighting the striking difference from the heritability pattern observed for disease severity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Genetic predisposition may not have the same biological consequences as environmental changes (through policy), such that the predicted effect may not be realized.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    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.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DYSF functions mainly characterized in skeletal muscle where it participates in calcium-mediated membrane repair and regeneration.

    “Although widely expressed, its functions are mainly characterized in skeletal muscle where it participates in calcium-mediated membrane repair and regeneration22.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Bansal, D. et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168–172 (2003). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The instrumental variable assumption of no horizontal pleiotropy holds.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    We have not tested the robustness of these findings to alternative measures of educational attainment or additional proxies of neurocognitive reserve.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    Disease modifying therapy was not included as it is not a confounder and may instead introduce collider bias.

    “Disease modifying therapy was not included as it is not a confounder (i.e. does not influence genotype) and may instead introduce collider bias57.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recessive pathogenic variants in DYSF lead to muscular dystrophies.

    “Recessive pathogenic variants lead to muscular dystrophies (OMIM 254130, 253601, 606768).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites OMIM 254130, 253601, 606768

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

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Our findings may have broader implications for neurodegeneration.

    “Our findings identify CNS resilience and reserve as likely determinants of MS progression, and may have broader implications for neurodegeneration.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The observations are in concordance with the proposed enhanced penetrance of monogenic causes of neurological disease reported to result from comorbidity with MS.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    EDSS has several shortcomings including its non-linear ordinal nature, variability between raters, overemphasis on ambulation, and inadequate capture of cognitive impairment.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    In survival analyses, events could only be observed at clinic visits and not in real-time.

    “In the survival analyses, events could only be observed at clinic visits and not in real-time.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Collider bias may occur when considering risk factors affecting both disease onset and progression.

    “Also, collider bias may occur when considering risk factors affecting both disease onset and progression.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mutations in PIGC can lead to intellectual disability and epilepsy.

    “Variant rs149097173 is also intronic to PIGC, mutations in which can lead to intellectual disability and epilepsy25.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Observing events only at clinic visits may bias survival time estimates from clinical settings where follow-up intervals can vary.

    “This may bias survival time estimates from clinical settings where follow-up intervals can vary.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Pathological characterization was undertaken blind to genotype status.

    “Pathological characterization was undertaken blind to genotype status.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The proportional hazards assumption was examined by inspection of scaled Schoenfeld residuals.

    “The proportional hazards assumption was examined by inspection of scaled Schoenfeld residuals.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    P values < 0.0083 were considered significant following Bonferroni correction for the number of variants and outcomes tested.

    “P values < 0.0083 were considered significant following Bonferroni correction for the number of variants and outcomes tested.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    P values less than 0.025 were considered significant (adjusting for two pathological variables).

    “P values less than 0.025 were considered significant (adjusting for two pathological variables).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    We applied FDR correction for multiple testing within each enrichment analysis.

    “We applied FDR correction for multiple testing within each enrichment analysis, and FDR-corrected P < 0.05 were considered statistically significant.”
    Quote in the paperSubstantial claim
60 of 60

  • 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”
6 of 6

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”

1 of 1

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.

  • Figure caption gives a different genotype measure for rs149097173

    Minor

    The Extended Data Fig. 4 caption says its Cox-model hazard ratios used imputed allele dosage, but the Methods say hazard ratios for rs149097173 were calculated using carrier status.

  • PIGC expression figure is cited as a genetic-correlations figure

    Minor

    The Extended Data Fig. 6 caption directs readers to Fig. 8 for PIGC expression, but Fig. 8 is labeled as genetic correlations. PIGC expression is instead the subject of Extended Data Fig. 7.

2 of 2

Cites

Flagged first, then by citations

4 of the 115 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

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
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-06-28
Volume
619
Issue
7969
Pages
323-331
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-023-06250-x
PMC
PMC10602210
OpenAlex
W4382394400
Semantic Scholar
69e4ed42c45dbea6fe4d5c4bc9018e4a7b0c984f
Cited by
243
References
115
Citations by year
2026: 62 · 2025: 69 · 2024: 81 · 2023: 30 · 2022: 1
FWCI
40.76
Type
journal article
Language
en
Open access
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 › Pathology and Forensic Medicine › 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-13.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-13.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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