Genomic determinants of Multiple Sclerosis susceptibility in an ethnically diverse population

Multiple Sclerosis (MS) is a disorder of the brain and spinal cord which affects about 1 in 1000 people worldwide. In people with MS (pwMS), the immune system attacks the lining of nerve cells (myelin), leading to 'attacks' of disability which can last days-months, and a gradual accumulation of disability over time. Although there are many effective treatments for MS, there is still no cure. MS was previously thought to almost exclusively affect White people, but recent evidence suggests this is untrue: in the USA, the number of newly-diagnosed people with MS is now higher among African American individuals than individuals of White European ancestry.

Most of our understanding of how genes contribute to MS risk comes from studies of individuals of European descent. The largest genetic association study to date revealed over 200 sites in the genome associated with MS, but it remains unclear whether these insights - from an exclusively European cohort - apply to individuals from different ethnic backgrounds. Understanding how genes contribute to MS risk in different populations has important implications for predicting, preventing, and treating MS among individuals from ethnic minority backgrounds. In addition, as individuals of African ancestry tend to have a more aggressive disease course than individuals of European ancestry, understanding the genetic basis for this difference may help to explain what causes and drives MS progression in all individuals.

In this study, we attempt to perform the largest genetic association study of MS among Black, Asian, and Minority Ethnic (BAME) individuals to date in the UK. We will collect genetic information from people with MS and healthy controls from BAME backgrounds, and we will systematically search for genetic variants more common in the people with MS. We will use a variety of techniques to see which genes cause MS in BAME people and whether the genes identified in people of European descent have the same or different effects in this population. We will then explore these findings to look for new drug targets, to improve prediction of MS, and to help disentangle whether various other risk factors for MS - such as childhood obesity and low vitamin D levels - are truly causal risk factors for MS in BAME populations.

We anticipate that this research will advance our understanding of what causes MS in BAME individuals, and may have important implications for our understanding of the causes of MS more broadly.

Multiple Sclerosis (MS) is a complex autoimmune disease characterised by inflammatory neurodegeneration of the brain and spinal cord. Despite advances in our understanding of the pathobiology of MS and the advent of rationally-designed monoclonal antibody therapies, there is no cure for MS nor is there any effective strategy available for preventing the onset of disease.

Consortium efforts have revealed over 200 autosomal loci which collectively explain a large proportion of MS heritability in individuals of European descent. However, it remains to be clarified whether the same genetic architecture accounts for MS susceptibility among individuals from other ethnic backgrounds.

We intend to perform the largest genetic association study of MS in individuals of non-European descent in the UK. The main goal of the study is to delineate the genetic architecture of MS in a diverse UK population, which we expect will reveal both substantial overlap with, and interesting divergence from the architecture described in Europeans. We will achieve this goal by recruiting from multiple collaborating academic centres, the UK MS Register, the UK MS Society, and via specific patient-led groups. We will use control data from the diverse East London Genes and Health project, UK Biobank, and ALSPAC. To estimate ethnicity-specific effects of genetic variants on MS risk, we will use the complementary approaches of admixture mapping and GWAS controlling for local ancestry. We will interpret these findings using standard annotation techniques, polygenic risk score profiling, and mendelian randomisation. Altogether, we hope to extend the understanding of MS genetics in a diverse UK population, which has important biological and clinical applications for the understanding of disease pathogenesis, development of prediction algorithms, and overall for the representation of previously marginalised groups in contemporary genetic research.