The Genetic Basis of Multiple Sclerosis Severity Suggests Central Nervous System Involvement
Adil Harroud1,2
1On behalf of MultipleMS, International Multiple Sclerosis Genetics Consortium, 2Weill Institute for Neurosciences, University of California San Francisco
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.


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.


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.


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 (rg=0.17), with none of 218 MS susceptibility variants influencing ARMSS score. 

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.