A groundbreaking UK study has uncovered shared genetic risk factors for multiple sclerosis (MS) across diverse ancestries, challenging the Euro-centric focus of previous research and paving the way for more inclusive diagnostics and treatments. Led by researchers at Queen Mary University of London (QMUL), the investigation analyzed data from thousands of participants, revealing that many genetic variants previously identified in European populations also play a role in South Asian and African ancestries.
This discovery not only highlights common biological mechanisms driving MS but also identifies ancestry-specific nuances, such as a protective variant more common in South Asians. As MS affects over 150,000 people in the UK and 2.9 million worldwide, these findings from the UK's higher education sector underscore the importance of diverse data in advancing medical science.
🔬 The ADAMS Project: Pioneering Diverse MS Research in UK Universities
The study stems from the Ancestrally Diverse MS (ADAMS) project, a collaborative initiative based at QMUL's Barts and The London School of Medicine and Dentistry. ADAMS specifically recruits people with MS (pwMS) from non-White British backgrounds, addressing a critical gap in genetic research where over 90% of prior MS studies focused on European ancestry populations.
Researchers combined genetic data from 676 pwMS in ADAMS with 2,426 MS cases and 27,640 controls from the UK Biobank, a vast repository managed by the University of Manchester and partners. Genetic ancestry was inferred using principal component analysis (PCA) and random forest classifiers trained on global reference panels, ensuring accurate grouping into South Asian (SAS), African (AFR), and European (EUR) ancestries.
Genotyping used the Illumina Global Screening Array, with imputation against the Haplotype Reference Consortium (HRC) panel tailored for multi-ancestry analysis. Genome-wide association studies (GWAS) employed REGENIE for mixed logistic models, adjusted for sex and principal components, while human leukocyte antigen (HLA) alleles were imputed with HIBAG and validated via SNP2HLA.
MS Background: Prevalence and Disparities in the UK and Beyond
Multiple sclerosis is a chronic autoimmune disease where the immune system attacks the myelin sheath insulating nerve fibers in the central nervous system, leading to symptoms like fatigue, vision loss, mobility issues, and cognitive impairment. In the UK, prevalence is approximately 203 per 100,000, affecting around 150,000 people, with incidence rates of 8-9 per 100,000 person-years, higher in women (2-3 times) and peaking at ages 20-40.
Traditionally viewed as more common in people of Northern European descent, recent UK data shows lower prevalence in Black (59% lower) and South Asian (84% lower) populations compared to White groups in areas like east London. However, Black pwMS often experience more severe disability progression, highlighting environmental, socioeconomic, and genetic interactions. Globally, MS affects 2.9 million, with rising incidence in non-European populations possibly due to improved diagnosis and lifestyle changes.
Understanding genetic underpinnings is crucial, as heritability estimates 30-50%, with over 200 risk loci identified, predominantly from European cohorts. This study bridges that gap, informing UK universities' role in equitable health research.
Key Findings: Strong Concordance in Genetic Risk Across Ancestries
The GWAS revealed genome-wide significant signals in the major histocompatibility complex (MHC) region for all ancestries. For SAS, the lead variant chr6:32635095:G:C near HLA-DQA1 had OR=1.7 (p=4.2e-8); for AFR, chr6:32593550:T:C near HLA-DRB1, OR=1.7 (p=1.2e-5).
- Suggestive non-MHC loci in SAS included ABCA4 (OR=2.73, p=3.27e-5) and AUTS2 (OR=0.57, p=2.36e-5).
- AFR showed 18 suggestive loci, e.g., RAI14 (OR=2.11, p=3.41e-7).
European risk alleles were over-represented in SAS (ρ=0.46, p=8.3e-9) and AFR (ρ=0.35, p=2.5e-5) cases, indicating shared pathways despite varying effect sizes.
MHC and HLA: Immune Drivers Consistent Yet Nuanced
The MHC, encoding immune-related genes, dominated associations. HLA-DRB1*15:01, the top MS risk allele (OR~3 in EUR), showed similar effects across groups but lower population-attributable fraction (PAF) in SAS (8.8%) and AFR (2.9%) due to rarity (vs. 30-40% in EUR).
Other shared risks: HLA-DPB1*10:01 (OR=3.1 SAS), HLA-B*37:01 (OR=2.2 SAS). Protective: HLA-DRB1*13:01 (OR=0.4 SAS). Notably, SAS-enriched HLA-A*33:03 emerged as protective, missed in EUR studies.
This underscores HLA's central role while revealing ancestry-modulated frequencies.
Photo by Fallon Michael on Unsplash
Polygenic Risk Scores: Promising but Limited in Non-Europeans
Polygenic risk scores (PRS) from a large European MS GWAS (14,802 cases) explained 9.6% liability in EUR, but only 3.9% in SAS (p=1e-4) and 1.9% in AFR (p=2e-4). Scores shifted cases toward higher risk, with monotonic OR increases by quartile.
Lower performance stems from allele frequency differences and linkage disequilibrium (LD) variations. Including MHC improved scores slightly. This highlights PRS recalibration needs for diverse groups to aid risk stratification and trials.
A Protective Variant: HLA-A*33:03 in South Asians
A standout discovery: HLA-A*33:03, frequent in SAS (~10-15%), protective against MS (suggestive OR<1). Absent in EUR cohorts, it exemplifies missed insights from homogeneous studies. Similar SAS enrichments in other alleles suggest adaptive immune histories influencing modern disease risk.
Implications for Diagnosis, Treatment, and Health Equity
Shared genetics validate universal therapies like ocrelizumab or siponimod targeting immune pathways. However, ancestry-tuned PRS could enable precision screening, earlier intervention in high-risk non-EUR groups where diagnosis delays exacerbate disability.
For UK higher ed, this bolsters calls for diverse biobanks. MS Society notes Black pwMS face worse trajectories; genetics explain part, but access disparities loom. MS Society UK funds ADAMS to ensure equitable progress.
Treatment implications: HLA-informed therapies (e.g., alemtuzumab safety) may vary; diverse trials needed.
Challenges: Underpowered Signals and Data Gaps
Small non-EUR samples limited novel discoveries (no genome-wide significant non-MHC hits). Imputation accuracy varies; direct HLA sequencing ideal. Batch effects mitigated but potential. Self-reported MS phenotypes lack validation.
UK MS prevalence lower in SAS/AFR, but rising diagnoses suggest under-recognition. Future: larger cohorts like expanded UKB/ADAMS for trans-ancestry meta-GWAS.
Expert Insights from QMUL and MS Community
Lead Prof. Ruth Dobson (QMUL): "MS genetics has been overwhelmingly European-based. Diversity improves science and fairness."
Dr. Benjamin Jacobs (QMUL): "Diversity reveals hidden risk factors and equitable tools." MS Society's Caitlin Astbury: "ADAMS leads diverse inclusion for global benefits."
Funded by MRC, MS Society; preprint on medRxiv, full in Neurology.
Photo by DeeDee Wang on Unsplash
UK Higher Education's Role in Global MS Research
QMUL's Preventive Neurology Centre exemplifies UK unis' leadership. Collaborations with UKB (Manchester-led) enable massive datasets. This study, part of QMUL's MS portfolio, attracts funding, PhDs, postdocs—see research jobs.
Impacts: Trains diverse scientists, boosts spinouts (e.g. PRS apps), positions Europe as inclusive research hub amid US/China competition.
Future Outlook: Toward Universal MS Prediction Models
Larger multi-ethnic GWAS (e.g. IMSGC expansions) will refine PRS, uncover modifiers. Ancient DNA links MS risk to steppe herders (2024 Nature study). Integrate environment (EBV, smoking, vitamin D) for holistic risk.
For patients: Better screening, personalized therapies. For academia: More diverse recruitment, ethical PRS deployment. UK leads; explore opportunities at European higher ed jobs.