Ancient genomes reveal origins of multiple sclerosis risk in Europe

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In a recent study published in Nature, researchers investigated the variables contributing to geographical heterogeneity in multiple sclerosis (MS) prevalence and the impact of genetic and environmental factors on the disease's development.

Study: Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations. Image Credit: Dorxela/Shutterstock.com
Study: Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations. Image Credit: Dorxela/Shutterstock.com

Background

Multiple sclerosis is a neurological condition most frequent in Northern Europe, with little known about its hereditary risk. The condition affects the brain and spinal cord, and the prevalence varies by ethnicity and geographic area. Researchers hypothesize that gene-gene and gene-environment interactions cause multiple sclerosis, with external triggers starting a chain reaction in genetically sensitive individuals.

Environmental and lifestyle variables contribute significantly to illness risk, accounting for approximately 30% of total disease risk. The European genetic origin may explain some global variance in multiple sclerosis prevalence among admixed groups.

About the study

In the present study, researchers used a vast ancient genomic dataset spanning between the Mesolithic and Bronze Ages with Medieval as well as post-Medieval Age genomes to calculate current European ancestry relative to ancestral populations. They investigated whether polymorphisms associated with elevated MS risks underwent positive selections and lifestyle-specificity of the selection targets.

The study examined environmental factors that might have led to the selection of risk variations, such as pathogen exposure and human subsistence practice. The team evaluated ancestry at particular loci ('local ancestry') for 410,000 white British individuals registered with the United Kingdom Biobank (UKBB) using reference panels of 318 deoxyribonucleic acid (DNA) samples from the Neolithic and Mesolithic, inclusive of steppe pastoralists.

The team calculated anomaly scores by comparing ancestry at single-nucleotide polymorphisms (SNPs) to genome-level ancestries in the UKBB. The human leukocyte antigen (HLA) site is significantly related to autoimmune disorders such as multiple sclerosis and rheumatoid-type arthritis (RA), characterized by systemic inflammation that predominantly affects body joints.

The collection contains 1,750 imputed diploid shotgun-sequenced ancient genomes, 1,509 of which belong to Eurasia, and combined with current data, they created a nearly complete transect from 10,000 years ago to the present.

The researchers investigated whether ancestry could predict phenotypes and created a new summary measure termed linkage disequilibrium of ancestry (LDA). They investigated LD-pruned MS-associated SNPs that exhibited statistically significant evidence for selection in one or more ancestries using CLUES (n = 32) and had a genome-wide meaningful trait relationship. The team compared the findings for MS to those for RA, a systemic inflammatory disease renowned for its distinctive joint abnormalities.

They performed a thorough literature search for pleiotropic effects of LD-pruned SNPs that exhibited statistically significant evidence of selection to understand the factors underlying the higher genetic risk in hunter-gatherer groups and subsequent negative-type selection.

Results

The genetic risk for multiple sclerosis arose among pastoralists from the Pontic Steppe who were carried to Europe some 5,000 years ago via Yamnaya-related migration. Positive selection of these MS-associated immunogenetic variations occurred within the steppe population and subsequently in Europe, most likely due to pathogenic difficulties coinciding with altered nutrition, lifestyle, and population density. The LCT/MCM6 area on the second chromosome, recognized as controlling lactase persistence, and the HLA region on the sixth chromosome revealed the most extreme ancestry compositions.

Steppe ancestry showed the highest risk ratio at all HLA SNPs for MS. The farmer and outgroup ancestries were frequently the most protective, indicating that a steppe-derived haplotype at these sites increases MS risk. Steppe heritage had the highest ARS for MS, followed by Caucasus hunter-gatherers (CHG), western hunter-gatherers (WHG), and eastern hunter-gatherers (EHG) ancestry; farmer and outgroup ancestry had the lowest ARS. As a result, steppe ancestry has the highest risk for MS across related SNPs.

The study population of self-identified white British individuals was somewhat underpowered concerning MS (1,949 cases and 398,049 controls; 0.49% prevalence), although MS showed associations in the HLA region to steppe and farmer ancestry. Local ancestry explained much more variance than genotypes in three out of four main LD blocks within the HLA region.

The team found evidence that disease risk was selectively higher between 5,000 and 2,000 years ago, with statistically significant selection signals in the WHG, EHG, and CHG routes but not in the ANA path.

The finding was most certainly related to the steppe's pastoralist population with approximately equal amounts of EHG and CHG ancestry. They uncovered a specific ancestral risk profile for RA, with HLA-DRB1*04:01 being the most significant genetic risk factor. WHG and EHG ancestry frequently gave the highest risk at SNPs related to RA, contributing the most risk overall. Across all pathways, most chosen SNPs showed associations with protection against specific pathogens and infectious diseases.

Conclusion

Overall, the study findings showed that the Neolithic and Bronze Age periods significantly influenced current immune responses and the likelihood of having MS in a changing environment. Extreme lifestyle changes led to a varied genetic lineage over 10,000 years, contributing to the highest genetic risk for MS in current times. Positive selection coincided with pastoralist lifestyles in the Pontic-Caspian steppe, and continued selection in admixed populations in Europe led to this heritage.

The study addressed the dispute over the north-south gradient in MS incidence in Europe, arguing that pathogen-human co-evolution resulted in high and varied genetic ancestry-specific selection on immune response genes.

Journal reference:
  • Barrie, W., Yang, Y., Irving-Pease, E.K. et al. Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations. Nature 625, 321–328 (2024). https://doi.org/10.1038/s41586-023-06618-z
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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