A higher burden of multiple sclerosis genetic risk confers an earlier onset

Multiple sclerosis is a neurodegenerative, autoimmune disease characterized by inrreversible neurological disability. The age at onset of multiple sclerosis is an objective and influential predictor of the evolution of multiple sclerosis independent of disease duration. Little is known about the mechanisms contributing to variation in onset age of multiple sclerosis, though HLA-DRB1*15:01 , the predominant risk variant, confers an earlier onset. Here we present an age at onset genome-wide association analysis for 9.2 million variants, including gene-based and pathway enrichment analyses, for 3,495 cases who were non-Latinx white with onset ≥18 years. We investigated whether a higher burden of multiple sclerosis risk variants conferred an earlier age at onset for combinations of HLA-DRB1*15:01 alleles and quintiles of a genetic risk score for 200 risk variants that reside outside the major histocompatibility complex. The study population had a mean age at onset of 32 years, 29% was male, and 46% were HLA-DRB1*15:01 carriers. HLA-DRB1*15:01 carriers were on average one year younger at onset than non-carriers ( p <0.001); a similar effect was observed for a 10-risk-allele increase in the genetic risk score ( p <1×10 -8 ). Those in the highest genetic risk score quintile (n=717) were on average 2.5 years younger at onset than those in the lowest quintile (n=698; p=1.2×10 -7 ). For those with the greatest genetic risk burden (highest genetic risk score quintile with two HLA-DRB1*15:01 alleles) were on average five years younger at onset ( p =0.002) than those with the lowest genetic risk burden (lowest genetic risk score quintile with no HLA-DRB1*15:01 alleles). There was an apparent inverse relationship between the genetic multiple sclerosis risk burden and age at onset of multiple sclerosis ( p <5×10 -8 ). We did not observe any individual variants reaching genome-wide significance in the genome-wide association analysis of age at onset. The most significantly associated independent genic loci ( p <5×10 -6 ) were located within HLA-DQB1, COL21A1, LINC01484, UBR3 , and CSMD1 . At the gene-level, the most significant associations ( p <5×10 -5 ) were for SSB, TRAFD1, HECTD2, MMP8, NAA25 and UBR3 . There was an enrichment of genes involved in adaptive and innate immunity, specifically genes in the complement pathway, and genes involved in synapses and collagen biosynthesis. In summary, we demonstrated a significant gradient between elevated genetic risk burden and an earlier onset of multiple sclerosis.