Genetic Threads of Multiple Sclerosis in Diverse Populations
A recent study has shed light on the genetic factors influencing Multiple Sclerosis (MS) susceptibility in individuals with South Asian and African ancestries. By delving into the genetic architecture of MS in these underrepresented groups, researchers aim to improve genetic risk prediction, pinpoint causal variants, and ultimately, identify potential drug targets.
Why Study MS Genetics in Diverse Populations?
* Limited Representation: Most MS genetic studies have primarily focused on populations of European ancestry.
* Equitable Risk Scores: Studying diverse ancestral populations is crucial for ensuring that genetic risk scores for predicting MS perform equally well across different groups.
* Understanding Disease Mechanisms: Analyzing the genetic underpinnings in various populations can refine the understanding of how genetic variation contributes to MS susceptibility.
The ADAMS Project: A Multi-Ancestry UK Cohort
The study, known as the ADAMS project (A Genetic Association study in Diverse Ancestries of Multiple Sclerosis), involved a UK-based cohort of individuals with MS from diverse ancestral backgrounds. Participants were recruited through clinical sites, online platforms, and the UK MS Register.
* Data Collection: Researchers collected extensive phenotype data using standardized questionnaires, covering demographics, MS history, risk factors, and measures of physical disability.
* Genetic Analysis: DNA was extracted from saliva samples, and participants were genotyped using a commercial genotyping array. The genetic data from the ADAMS cohort was combined with data from the UK Biobank, which served as a source of controls.
Key Findings
* MHC Associations: The study identified genetic variants within the Major Histocompatibility Complex (MHC) associated with MS susceptibility in both South Asian and African ancestries. The lead variant in the South Asian group was near the HLA-DRB1 gene, while in the African group, it was near the HLA-A gene.
* Shared Disease Mechanisms: The genetic architecture of MS susceptibility shows strong concordance across ancestral groups, suggesting shared disease mechanisms. European-ancestry susceptibility alleles were over-represented in cases from both ancestries, indicating a common genetic basis for MS across different populations.
* Polygenic Risk Scores (PRS): European-derived genetic risk scores could distinguish MS cases from controls in South Asian and African ancestries but performed less effectively than in European ancestry cohorts. This suggests that while there is overlap in the genetic factors influencing MS across different ancestries, there are also ancestry-specific genetic effects.
* HLA Allelic Associations: Several classical HLA alleles showed suggestive associations with MS susceptibility in both ancestries. In the South Asian cohort, HLA-DPB1*10:01, HLA-B*37:01, HLA-A*26:01, HLA-DRB1*15:01, HLA-A*23:01 and HLA-DRB1*04:01 showed risk-increasing effects, while HLA-DRB1*13:01 and HLA-DQB1*06:03 had protective effects. In the African cohort, HLA-A*66:01 showed risk-increasing impact.
Statistical methods
* Genome-wide association studies (GWAS): GWAS were conducted within each ancestry group to identify genetic variants associated with MS susceptibility. Logistic regression models were used to account for population structure and sex.
* HLA allele imputation: Classical HLA alleles were imputed using HIBAG R package and validated using SNP2HLA. Association between common HLA alleles and MS risk was tested within each ancestry using logistic regression models.
* Polygenic risk score profiling: Risk scores were derived using common variants from European-ancestry GWAS and applied to the South Asian and African ancestry participants.
Implications and Future Directions
The study highlights the importance of including diverse populations in genetic studies of MS. By identifying genetic variants and HLA alleles associated with MS in non-European ancestries, researchers can:
* Improve Risk Prediction: Develop more accurate and equitable genetic risk scores for MS across different populations.
* Fine-Map Causal Variants: Refine the understanding of how genetic variation contributes to disease susceptibility.
* Identify Drug Targets: Enhance the identification of potential drug targets for MS.
The authors emphasize that larger studies in diverse populations are needed to fully understand the genetic basis of MS and to translate these findings into clinical applications.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
jacobs, B. M., Schalk, L., Tregaskis-Daniels, E., Scalfari, A., Nandoskar, A., Dunne, A., ... & Dobson, R. (2025). Genetic determinants of Multiple Sclerosis susceptibility in diverse ancestral backgrounds. medRxiv, 2025-01.
