Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

Abstract

The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.

Genome‐wide association studies of multiple sclerosis

“…This resulted not only in the description of multiple class II HLA‐DRB1 and HLA‐DRQ1 classical alleles imputed from SNP genotypes, but also epistatic interactions between HLA‐DQA1*01:01 and HLA‐DRB1*15:01 and between HLA‐DQB1*03:01 and HLA‐DQB1*03:02. These results raise certain functional questions, for example why the protective effect of HLA‐DQA1*01:01 only manifests in the presence of the HLA‐DRB1*15:01 risk allele 50, 51. Several variants outside the classical regions of the MHC (both class I and class II) were also shown to be independently associated, suggesting biological functions beyond antigen display underlie the MHC risk effects.…”

Feasibility study for remote assessment of cognitive function in multiple sclerosis

“…There is a strong genetic contribution to MS; the human leukocyte antigen (HLA)-DRB1 locus within the major histocompatibility complex (MHC), specifically the DRB1*15:01 allele, confers the strongest risk 30 . TICS-M scores did not vary by HLA-DRB1*15:01 carrier status in MS cases; no association was observed.…”

Role of a Novel Human Leukocyte Antigen-DQA1*01:02;DRB1*15:01 Mixed Isotype Heterodimer in the Pathogenesis of “Humanized” Multiple Sclerosis-like Disease

“…Genome-wide association and candidate gene studies have suggested that the greatest effects on MS risk conferred by the DR15 haplotype are driven by the HLA-DRB1*15:01 allele (5,6,41,42). However, linkage disequilibrium in the HLA-class II region makes it difficult without functional studies to distinguish whether the functionally relevant effect on MS derives only from the DRB1*15:01 or also from the neighboring genes in the HLA-DR15 region, from their combination, or from their epistatic interaction.…”