Assessing HLA-associated Multiple Sclerosis risk using multi-ethnic imputation in Swedish cohorts

Sammanfattning

Introduction: Multiple sclerosis (MS) is a chronic inflammatory disease influenced by both environmental and genetic factors. Among genetic determinants, HLA-DRB1*15:01 is established as a major MS risk allele, while the contribution of HLA-A*03:01 and its potential effects on clinical features remain less clearly defined. Aim: To provide an assessment of independent HLA genetic associations with MS risk using an updated multi-ethnic reference HLA imputation approach in large Swedish cohorts. As a secondary aim, to explore associations between selected haplotypes and MS clinical phenotypes. Methods: Genetic data from three large Swedish cohorts obtained from the Swedish MS-register, including 13 314 MS patients and 8874 matched controls were analyzed. HLA alleles were imputed using SNP2HLA-TAPAS and a multi-ancestry reference panel. Quality control excluded variants and individuals with low call rates. Statistical significance was determined with Chi-square, Kruskal–Wallis and Wilcoxon test. Results: Using a multi-ethnic panel improved the accuracy of HLA-DRB1*15:01 imputation. HLA-DRB1*15:01 was also significantly overrepresented among MS patients in all cohorts and associated with earlier age at onset but showed no significant association with MS subtype. HLA-A*03:01 was also more frequent in MS patients but showed no significant association with age at onset or MS subtype. Neither HLA-DRB1*15:01 or HLA-A*03:01 accounts for the higher incidences in women. Results were consistent across cohorts. Conclusion: We show that HLA-DRB1*15:01 can now be reliably inferred from GWAS data, overcoming prior imputation limitations, and enabling large-scale MS studies with strong associations to both disease risk and clinical phenotypes.