Abstract Details

Title The Genetic Basis of Multiple Sclerosis Severity Suggests Central Nervous System Involvement

Topic Multiple Sclerosis

Presentation(s) S5 - COVID and MS Basic Science (4:18 PM-4:30 PM)

Poster/Presentation
Number 005

Background The mechanisms underlying MS disease severity and its wide heterogeneity remain poorly understood. A persistent challenge has been determining whether genetic variation influences these traits, despite comprehensive genetic characterization of MS susceptibility.

Objective To determine the genetic architecture of multiple sclerosis (MS) disease severity, as captured by the age-related multiple sclerosis severity (ARMSS) score, and disability worsening.

Design/Methods In a population of in 12,584 people with MS (pwMS), we estimated the proportion of ARMSS score variance attributable to additive common genetic variation (SNP-heritability) using 7.8 million variants. Then, we interrogated for enrichment in hundreds of tissues and cell types based on linkage disequilibrium score regression (LDSC) and gene expression annotations. We performed a genome-wide association study (GWAS) and attempted replication in an independent cohort of 9,805 pwMS. Discovered loci were tested for association with 6-month confirmed disability worsening (CDW) over 63,900 visits. Last, we compared the genetic structure of MS severity and susceptibility.

Results We found evidence for a genetic basis for MS severity, with an estimated SNP-heritability of 10%. In contrast to MS susceptibility, robust tissue-level enrichment was apparent in the brain and cervical spinal cord (FDR<0.05), but not in immune cells. We identified a novel locus (p<5x10^-8) and confirmed this in the replicate population. The lead variant was not in linkage with MS susceptibility variants (r²<0.003). Survival analysis revealed an association between the risk allele and faster CDW (HR=1.13, p=0.007). We observed only weak genetic correlation between MS severity and susceptibility (r_g=0.17), with none of 218 MS susceptibility variants influencing ARMSS score.

Conclusions

We report the genetic contributions to MS severity, highlighting a novel locus influencing progression of disability, and describe a distinct genetic architecture from MS susceptibility. While genetic associations with the latter are mediated via immune cells, our data point to implication of the central nervous system for MS severity.

Authors/Disclosures
Adil Harroud, MD (McGill University) PRESENTER	Dr. Harroud has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Dr. Harroud has received research support from National Multiple Sclerosis Society. The institution of Dr. Harroud has received research support from Multiple Sclerosis Society of Canada.