Genetic Determinants of Multiple Sclerosis Susceptibility in People From Diverse Ancestral Backgrounds

The genetic basis of multiple sclerosis (MS) susceptibility has been studied extensively in European (EUR) ancestry populations. The aim of our study was to determine the genetic architecture of MS susceptibility in people of South Asian (SAS) and African (AFR) genetic ancestral backgrounds.

We recruited and genotyped a cohort of ancestrally diverse people with MS (pwMS) from across the United Kingdom. Cases were combined with controls from the UK Biobank (UKB). After genetic ancestry inference, we performed within-ancestry case-control genetic association studies of MS susceptibility, exploring single nucleotide variants and imputed classical human leukocyte antigen alleles.

We analyzed genetic data from 676 pwMS from our cohort (median age = 45.7 years, 71.7% female genetic sex), 2,426 pwMS from the UKB (median age = 55.0 years, 72.3% female), and 27,640 UKB controls (median age = 54.0 years, 52.5% female). Genetic variants within the Major Histocompatibility Complex were associated with MS susceptibility across all ancestries (SAS: lead SNP chr6:32635095:G:C, odds ratio [OR] = 1.7, p = 4.2 × 10^-8, nearest gene HLA-DQA1; AFR: lead SNP chr6:32593550:T:C, OR = 1.7, p = 1.2 × 10^-5, nearest gene HLA-DRB1). EUR ancestry susceptibility alleles were over-represented in cases from both ancestries, with the degree of concordance stronger for the SAS (ρ = 0.46, p = 8.3 × 10^-9) than the AFR (ρ = 0.35, Spearman p = 2.5 × 10^-5) ancestry cohort. EUR-derived genetic risk scores performed better than chance but less well than in EUR ancestry cohorts, explaining 3.9% (SAS, p = 1.0 × 10^-4) and 1.9% (AFR, p = 2.0 × 10^-4) of the liability to MS, contrasting with 9.6% (empirical p = 1.0 × 10^-4) in the EUR cohort. Several classical human leukocyte antigen (HLA) alleles associated with MS in EUR ancestry populations show similar effects in SAS and AFR ancestry cohorts, including HLA-DRB1*15:01; however, the population-level risk explained by this allele is lower in SAS (8.8%) and AFR (2.9%) cohorts than in EUR cohorts due to allele frequency. We found some evidence for a protective role for the SAS-enriched HLA-A*33:03 allele in the SAS cohort, which has not been previously described.

The genetic architecture of MS susceptibility shows strong concordance across ancestral groups suggesting shared disease mechanisms. Larger studies in diverse populations are likely to enhance our understanding of how genetic variation contributes to MS susceptibility in people of all ancestral backgrounds.