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GP.1 The genetic basis of multiple sclerosis severity

Published online by Cambridge University Press:  24 June 2022

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Abstract

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Background: The mechanisms underlying the severity and wide heterogeneity of multiple sclerosis (MS) remain poorly understood. A persistent challenge has been determining whether genetic variation influences these traits. Methods: In 12,584 people with MS (pwMS), we estimated the proportion of age-related MS severity score variance attributable to additive genetic variation (SNP-heritability). Then, we interrogated for enrichment in hundreds of tissues and cell types using gene expression annotations. We performed a genome-wide association study (GWAS) using 7.8 million variants and attempted replication in an independent cohort of 9,805 pwMS. A subset of 8,325 pwMS was examined longitudinally over 54,113 visits. Results: We observed a 10% SNP-heritability for MS severity. In contrast to MS susceptibility, robust tissue-level enrichment was apparent in the brain and cervical spinal cord, but not in immune cells. We identified a novel MS severity locus (p<5×10−8) and confirmed this in the replicate population. The lead variant was associated with higher hazards of 6-month confirmed disability worsening (p=0.008) and faster EDSS worsening (p=0.002). Time to walking aid (EDSS 6.0) was 3.2 years earlier in homozygous risk carriers. Conclusions: This study identifies the first genetic modifier of MS progression, establishes the genetic contributions to its heterogeneity and describes a distinct genetic architecture from susceptibility.

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Copyright
© The Author(s), 2022. Published by Cambridge University Press on behalf of Canadian Neurological Sciences Federation