Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population

Abstract

The Major Histocompatibility Complex (MHC) makes the largest genetic contribution to multiple sclerosis (MS) susceptibility, with 32 independent effects across the region explaining 20% of the heritability in European populations. Variation is high across populations with allele frequency differences and population-specific risk alleles identified. We sought to identify MHC-specific MS susceptibility variants and assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals as well as 2435 Black and African American individuals. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have utilized the differing linkage disequilibrium patterns inherent to these populations to identify an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus with a decrease of ~5.5% in Hispanics and ~0.4% in African Americans. We have identified several susceptibility variants, including within the MICB gene region, which show global ancestry risk modification and indicate ancestral differences which may be due in part to correlated environmental factors. We have also identified several susceptibility variants for which MS risk is modified by local ancestry and indicate true ancestral genetic differences; including HLA-DQB1*06:02 for which MS risk for European allele carriers is almost two times the risk for African allele carriers. These results validate the importance of investigating MS susceptibility at an ancestral level and offer insight into the epidemiology of MS phenotypic diversity.

ADAMS project: a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the UK

“…To date, genome-wide screening efforts to identify determinants of MS risk in populations of non-European ancestry have only involved modest numbers of participants, thus providing limited statistical power 8. Unsurprisingly, none of these studies has identified new genome-wide significant associations, however the single nucelotide polymorphisms (SNPs) associated with MS susceptibility in genetically European populations have shown concordant effects on risk in populations of South Asian, African, Hispanic and ancestrally mixed backgrounds 9–16. It is inevitable that many of the variants of relevance in MS will differ in allele frequency between populations.…”

“…It is inevitable that many of the variants of relevance in MS will differ in allele frequency between populations. This will potentially result in differences in power to identify such variants in specific populations, emphasising the value of studying the genetic architecture of MS in diverse cohorts 16 17…”

“…This will potentially result in differences in power to identify such variants in specific populations, emphasising the value of studying the genetic architecture of MS in diverse cohorts. 16 17 …”

Inclusion of optic neuritis in dissemination in space improves the performance of McDonald 2017 criteria in Hispanic people with suspected multiple sclerosis

“…MS is a complex disease influenced by both genetic and environmental factors. Different patterns of risk and clinical expression have been associated with differing ancestry among patients with MS 20,21 and ON. 22 For example, genetic markers of native ancestry are significantly associated with ON as the presenting clinical event in a large Hispanic cohort.…”

Re-thinking race and geography in multiple sclerosis

“…Hispanic ancestry is a genetic admixture of mainly Native American/American Indian, European, and African ancestries 17 with differing proportions as a consequence of complex political, social, and migratory histories to regions. Genetic admixture differences within African American and Hispanic populations have been found to correlate with an individual’s risk of MS. 18 This highlights a central role for the inclusion of ancestry to complement future examinations where both global and local variant-specific ancestral risk modifications could influence prevalence or phenotypic differences across racial and ethnic groups. Several ongoing clinical trials that focus on underrepresented populations build on this observational data complementing race and ethnic self-identify with genetic data.…”