Genetic determinants of Multiple Sclerosis susceptibility in diverse ancestral backgrounds

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Abstract The genetic architecture of Multiple Sclerosis (MS) susceptibility has been extensively assessed in populations of European ancestry. Greater ancestral diversity in genetic analyses of MS susceptibility is needed to improve the utility of Multiple Sclerosis genetic risk scores, fine map causal variants underlying established associations, and thereby enhance the identification of drug targets. Here we report findings from a genetic study of Multiple Sclerosis susceptibility in an ancestrally-diverse United Kingdom-based cohort. Participants with Multiple Sclerosis were recruited via clinical sites, an online platform, and through the United Kingdom Multiple Sclerosis Register. Phenotype data were gathered using a standardised questionnaire. DNA was extracted from saliva samples obtained remotely or in person, and participants were genotyped using a commercial genotyping array. Following imputation, cases were combined with controls from the United Kingdom Biobank and subjected to stringent quality control and genetic ancestry inference. We defined two broad ancestral groups of South Asian and African ancestry. We performed within-ancestry case-control genome-wide association studies of Multiple Sclerosis susceptibility using logistic models accounting for population structure and sex. We examined both single nucleotide variants and imputed classical Human Leukocyte Antigen alleles. We curated two ancestrally-matched case-control genetic datasets (South Asian ancestry: N Case =175, N Control =6744; African ancestry: N Case =113, N Control =5177). In both ancestries, we found genetic variants within the Major Histocompatibility Complex associated with Multiple Sclerosis susceptibility (South Asian ancestry: lead variant chr6:32600515:G:A on hg38 co-ordinates, Odds Ratio=1.84, nearest gene HLA-DRB1 , P= 4.6×10 −6 ; African ancestry: lead variant chr6:29919337:A:G, Odds Ratio=2.24, nearest gene HLA-A P= 4.3×10 −5 ). European-ancestry susceptibility alleles were over-represented in cases from both ancestries, with the degree of concordance stronger for the South Asian (ρ=0.31, P =8.1×10 −6 ) than African (ρ=0.1, P =0.3) ancestry cohort. European-derived genetic risk scores performed better than chance but less well than in European ancestry cohorts, explaining 1.6% (South Asian , P =1.0×10 −4 ) and 0.5% (African , P =0.08) of the liability to MS. 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.

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