Why is multiple sclerosis (MS) twice as common in Scandinavia as in the Mediterranean? A groundbreaking study published in Nature in January 2024, analysing ancient DNA from nearly 5,000 human skeletons, finally cracked this decades-old mystery. The answer lies in the migrations of Yamnaya pastoralists roughly 5,000 years ago, whose descendants, notably the Bell Beakers, spread across Europe genetic variants that once protected against livestock infections but now increase the risk of autoimmune diseases.
~1.2MEuropeans with MS
2×More common in the North than the South
233Genetic risk variants identified
~5,000Years of genetic legacy

The North, South Gradient: A Long-Standing Mystery

Multiple sclerosis is a neuro-inflammatory and neurodegenerative disease in which the immune system mistakenly attacks myelin, the protective sheath surrounding nerve fibres of the brain and spinal cord. With roughly 1.2 million people affected in Europe, it is the leading cause of neurological disability in young adults.

For decades, epidemiologists have observed a striking north, south gradient: MS prevalence increases nearly linearly with latitude, with the highest rates concentrated between 45° and 65° N. Hypotheses ranging from vitamin D deficiency, reduced sunlight, and environmental factors only partially accounted for this distribution. The missing piece of the puzzle lay in ancient DNA.

Key finding: Barrie et al. (2024) in Nature demonstrated that the genetic risk for MS is primarily carried by “steppe” (Yamnaya) ancestry, introduced into Europe roughly 5,000 years ago. The north, south MS gradient directly mirrors the steppe ancestry gradient in modern European populations.

MS Prevalence Across Europe

Data from the MS Barometer 2020 and the Atlas of MS reveal dramatic differences between European countries. North-western Europe, the direct heir of steppe migrations, has some of the highest MS rates in the world.

MS Prevalence in Europe - Choropleth map showing cases per 100,000 population by country
Figure 1, MS prevalence across Europe by country. The north, south gradient is striking, with the highest rates in Scandinavia, the British Isles, and Germany, and the lowest in the Balkans and Eastern Europe. Source: MS Barometer 2020 & Atlas of MS, 3rd Edition.

MS Prevalence by Country

Country Prevalence / 100k Region Category
Germany 299 Central Europe Very high
Sweden 215 Scandinavia Very high
Norway 212 Scandinavia Very high
Denmark 193 Scandinavia Very high
United Kingdom 190 British Isles Very high
Ireland 169 British Isles High
Czech Republic 168 Central Europe High
Netherlands 161 Western Europe High
France 155 Western Europe High
Belgium 155 Western Europe High
Finland 155 Scandinavia High
Switzerland 148 Central Europe Elevated
Austria 148 Central Europe Elevated
Poland 120 Eastern Europe Elevated
Iceland 120 Nordic Elevated
Estonia 115 Baltic Elevated
Italy 113 Southern Europe Moderate
Spain 100 Southern Europe Moderate
Hungary 89 Central Europe Moderate
Greece 70 Southern Europe Low
Bulgaria 62 Balkans Low
Croatia 59 Balkans Low
Portugal 56 Southern Europe Low
Romania 55 Eastern Europe Low
Serbia 53 Balkans Low
Ukraine 42 Eastern Europe Very low
Moldova 37 Eastern Europe Very low

The Steppe Migrations: From the Pontic Steppe to the Atlantic

To understand the present-day distribution of MS, we must travel back to the 4th millennium BCE, to the Pontic-Caspian steppe. This is where the Yamnaya lived, nomadic pastoralists who herded cattle and sheep, carrying a genetic ancestry distinct from the Neolithic farmers who then populated Europe.

~3300, 2600 BCE

Yamnaya culture, Nomadic pastoralists of the Pontic-Caspian steppe. Carried Y-chromosome haplogroup R1b-Z2103. Mixed Eastern Hunter-Gatherer (EHG) and Caucasus Hunter-Gatherer (CHG) ancestry. The first major carriers of MS risk variants.

~2900, 2400 BCE

Corded Ware culture, Expanded into Northern and Eastern Europe. ~75% steppe ancestry. Dominant haplogroup: R1a-M417/Z282. Not directly descended from Yamnaya despite shared steppe ancestry.

~2800, 2000 BCE

Bell Beaker phenomenon, Expanded across Western and Southern Europe. ~50% steppe ancestry. Dominant haplogroup: R1b-P312 (L21, U152, DF27). Massive population replacement, notably in Britain (~90% replacement by c. 2500 BCE).

~2000, 800 BCE

European Bronze Age, Stabilisation of mixed populations. Gradual admixture between steppe descendants and Neolithic remnants. MS risk variants continued undergoing positive selection.

Key point: Although Yamnaya, Corded Ware, and Bell Beaker populations share steppe ancestry, their paternal lineages differ: R1b-Z2103 (Yamnaya), R1a-Z282 (Corded Ware), R1b-P312 (Bell Beaker). This suggests a common steppe origin but distinct migration trajectories, each carrying the same MS risk variants.

Steppe Ancestry & MS: A Striking Correlation

The study by Barrie et al. (2024) revealed a remarkable correlation between the proportion of steppe ancestry in modern populations and MS prevalence. The countries that received the most steppe ancestry via Bell Beaker and Corded Ware migrations are precisely those where MS is most common today.

Estimated Steppe Ancestry in Modern Europeans - Choropleth map showing percentage by country
Figure 2, Estimated steppe ancestry in modern European populations. Compare with Figure 1: the gradient is remarkably similar, with the highest steppe ancestry in the same regions that have the highest MS prevalence. Derived from Allentoft et al. 2024 & Haak et al. 2015.

? High steppe ancestry, High MS prevalence

Scandinavia, British Isles, Germany, Netherlands

Steppe ancestry: 45, 55%. MS prevalence: 155, 299/100k. Dominant haplogroups R1b-U106, R1b-P312, I1. Massive Neolithic population replacement in the 3rd millennium BCE.

? Low steppe ancestry, Low MS prevalence

Balkans, Sardinia, Southern Italy, Greece

Steppe ancestry: 15, 30%. MS prevalence: 37, 70/100k. Strong persistence of Neolithic farmer ancestry (EEF). Haplogroups J2, E-V13, G2a more frequent.

The Specific Role of Bell Beakers

Among the vectors of steppe migrations, the Bell Beaker phenomenon holds a central place in explaining the current distribution of MS across Western Europe. Unlike Corded Ware, which spread mainly into Northern and Eastern Europe, Bell Beakers covered an immense territory from Ireland to Sicily, from Scotland to Portugal.

Bell Beaker Genetic Profile

Steppe ancestry: ~50% on average (variable by region and phase)

Neolithic ancestry (EEF): ~40, 45%

WHG ancestry: ~5, 10%

Dominant Y-haplogroup: R1b-P312 (with subclades L21, U152, DF27)

British replacement: ~90% of the Neolithic population replaced by c. 2500 BCE

The case of Britain is particularly instructive. The arrival of Bell Beakers around 2500 BCE triggered a near-total population replacement, replacing the builders of Stonehenge with populations carrying high levels of steppe ancestry. This massive turnover largely explains why the British Isles today have some of the highest MS rates in the world (190/100,000 in the UK, 169 in Ireland).

In the Iberian Peninsula, replacement was more gradual and modern populations retain more Neolithic farmer ancestry, reflected in more moderate MS rates (100/100,000 in Spain, 56 in Portugal). Sardinia, which was largely spared from steppe Bell Beaker migrations, remains one of the European populations with the highest residual Neolithic ancestry.

The Genetic Mechanism: HLA and Positive Selection

The link between steppe ancestry and MS is not merely a statistical correlation. It rests on precise genetic mechanisms, identified through ancient DNA analysis.

The HLA complex and the DRB1*15:01 allele

The main genetic risk factor for MS is the HLA-DRB1*15:01 allele, located in the major histocompatibility complex (MHC) region on chromosome 6. Carriers of this allele face roughly 3-fold increased risk of developing MS. Barrie et al. demonstrated that this allele is preferentially carried on steppe ancestry haplotypes: at every MS-associated HLA locus, steppe ancestry showed the highest risk ratio.

Positive selection: MS-associated genetic variants underwent positive selection between 5,000 and 2,000 years ago (P = 1.02 × 10−5). This selection, favouring a more aggressive immune system, protected steppe pastoralists against infections transmitted by their livestock.

An advantage turned liability

The evolutionary explanation is elegant. The Yamnaya were herders living in close contact with cattle and sheep, exposed to numerous zoonotic pathogens. A more reactive immune system conferred a considerable survival advantage. The genetic variants that enhanced immune response, which we now identify as MS risk variants, were therefore favoured by natural selection.

This advantage persisted for millennia, including after arrival in Europe, where mixed populations continued herding. Only with modern lifestyle changes (improved hygiene, reduced pathogen exposure, processed diets) did these same variants become detrimental, predisposing carriers to autoimmune diseases, of which MS is the most prominent example.

“This means we can now understand and seek to treat MS for what it actually is: the result of a genetic adaptation to certain environmental conditions that prevailed in our prehistoric past.” , Professor Lars Fugger, co-author, University of Oxford

The Three Ancestries and Their Relationship to MS

The study decomposed the genetic risk for MS according to the three main ancestries that compose modern European populations. This decomposition reveals why certain regions are more affected than others.

Ancestry MS Risk Score Geographic Origin Current Distribution
Steppe (Yamnaya) Highest Pontic-Caspian steppe Peak in NW Europe (45, 55%)
CHG (Caucasus HG) High Southern Caucasus Component of steppe ancestry
EHG (Eastern HG) Moderate Russian plains Component of steppe ancestry
WHG (Western HG) Moderate Atlantic Europe Low everywhere (5, 15%)
Farmer (ANA + Neolithic) Lowest (protective) Anatolia / Fertile Crescent Peak in Southern Europe (50, 70%)

This table is telling: Neolithic farmer ancestry is the most protective, while steppe ancestry carries the highest risk. Southern European populations, with their strong Neolithic farmer component and lower steppe contribution, benefit from a relative “genetic shield” against MS. Conversely, north-western populations, heavily shaped by Bell Beaker and Corded Ware migrations, concentrate the risk variants.

Migration Routes and Transmission of Risk Variants

Steppe Pastoralist Migration Routes (3300, 2000 BCE) Pontic Steppe Yamnaya R1b-Z2103 Corded Ware R1a-Z282 • ~75% steppe Bell Beakers R1b-P312 • ~50% steppe British Isles ~90% replacement Scandinavia Central Europe Iberia Partial admixture Balkans Little steppe input Corded Ware expansion (N & E) Bell Beaker expansion (W & S) Origin
Figure 3, Diffusion routes of MS risk variants from the Pontic steppe. The two main waves, Corded Ware to the north-east and Bell Beakers to the west, each carried the same immunogenetic variants.

Beyond Genetics: Environmental Co-Factors

While the steppe ancestry gradient explains a major share of MS prevalence variation in Europe, environmental factors remain important. Several co-factors modulate the expression of these genetic risk variants.

Vitamin D

Vitamin D deficiency, more common at high latitudes, potentiates the steppe-derived MS risk variants.

Epstein-Barr Virus

Near-universal EBV infection is a recognised co-factor, potentially interacting with steppe-derived HLA variants.

Smoking

Tobacco independently increases MS risk and interacts with HLA region genetic variants.

Female Sex

Women are 2, 3 times more affected than men, a ratio relatively constant across Europe.

The interaction between steppe-derived genetic predisposition and these environmental factors creates a “fertile ground” for MS development. A Scandinavian carrying multiple risk variants inherited from Bell Beaker or Corded Ware ancestors, living at a latitude where sunlight is scarce and vitamin D deficiency common, accumulates risk factors synergistically.

Implications for Research and Treatment

The discovery of the steppe origin of MS genetic risk opens new therapeutic avenues. By understanding that MS results from an immune system “calibrated” to combat the infections of Bronze Age herders, researchers can develop targeted approaches that rebalance the immune response rather than simply suppressing it.

Furthermore, ancestral risk mapping enables personalised approaches to preventive medicine. Individuals with strong steppe ancestry in the HLA region could benefit from earlier screening and monitoring, particularly if they carry additional risk factors.

Conclusion: When Prehistory Illuminates Medicine

The story of MS is ultimately a story of migration, adaptation, and unintended consequences. Five thousand years ago, Yamnaya steppe pastoralists carried immune variants that protected them from livestock diseases. Their descendants, the Corded Ware to the north-east, the Bell Beakers to the west, spread these variants across the entire European continent.

The north, south MS gradient, long unexplained, faithfully mirrors the steppe ancestry gradient in modern Europe: high in the north-west (Scandinavia, British Isles, Germany), where Bell Beaker and Corded Ware populations massively replaced Neolithic farmers; low in the south (Balkans, Mediterranean), where Neolithic farmer ancestry predominates and provides relative protection.

This major discovery, made possible by ancient DNA analysis on an unprecedented scale, beautifully illustrates how paleogenomics can not only illuminate our past but also transform our understanding of present-day diseases and guide the therapies of tomorrow.

References

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