Do Cerebral Small Vessel Disease and Multiple Sclerosis Share Common Mechanisms of White Matter Injury?
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Brown, R., Traylor, M., Burgess, S., Sawcer, S., & Markus, H. (2019). Do Cerebral Small Vessel Disease and Multiple Sclerosis Share Common Mechanisms of White Matter Injury?. Stroke, 50 (8), 1968-1972. https://doi.org/10.1161/strokeaha.118.023649
Background and purpose The role of inflammation in ischaemic white matter disease is increasingly recognised, and further understanding of the pathophysiology might inform future treatment strategies. Multiple sclerosis is a chronic autoimmune condition in which inflammation plays a central role that also affects the white matter. We hypothesised that white matter injury might share common mechanisms and used statistical genetics techniques to assess whether having genetically-elevated WMH volume was associated with increased MS risk. Methods We investigated genetic association in two cohorts with MRI-quantified ischaemic white matter lesion volume (WMH in stroke; n=2,797 and UK Biobank; n=8,353) and 14,802 cases of MS and 26,703 controls from the International Multiple Sclerosis Genetics Consortium. We further performed individual level polygenic risk score calculations for MS and measures of structural white matter disease in UK Biobank. Finally we looked for evidence of overlapping risk across the whole genome. Results There was no association of genetic variants influencing MS with white matter hyperintensity (WMH) volume using summary statistics in the WMH in stroke cohort (relative risk score = 1.014; 95% confidence interval 0.936 – 1.110), or in the UK Biobank cohort (relative risk score = 1.030; 95% CI 0.932 – 1.117). Conversely, assessing the contribution of SNPs significantly associated with WMH on the risk of MS there was no significant association (relative risk score = 0.930; 95% CI 0.736 – 1.191). There were no significant associations between polygenic risk scores calculations; these results were robust to selection of SNPs at a range of significance thresholds. Whole genome analysis did not reveal any overlap of risk between the traits. Conclusions Our results do not provide evidence to suggest a shared mechanism of white matter damage in ischaemia and multiple sclerosis. We propose that inflammation acts in distinct pathways due to the differing nature of the primary insult.
Humans, Multiple Sclerosis, Polymorphism, Single Nucleotide, Aged, Middle Aged, Female, Male, Genome-Wide Association Study, Cerebral Small Vessel Diseases, White Matter
This study was supported by a programme grant from the British Heart Foundation (RG/16/4/32218). Hugh Markus is funded by a National Institute for Health Research (NIHR) Senior Investigator Award, and his work is supported by the Cambridge University NHS Trust Biomedical Research Centre. Stephen Burgess is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z).
British Heart Foundation (RG/16/4/32218)
Wellcome Trust (204623/Z/16/Z)
British Heart Foundation (RG/13/13/30194)
Medical Research Council (MC_UU_00002/7)
British Heart Foundation (RG/18/13/33946)
External DOI: https://doi.org/10.1161/strokeaha.118.023649
This record's URL: https://www.repository.cam.ac.uk/handle/1810/292482
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