Why do some people develop multiple sclerosis (MS) while others do not? Recent large genome-wide association studies (GWAS) have deepened our understanding of multiple sclerosis’ genetic landscape [1]. Researchers have related over 233 independent genetic variants to an increased risk of developing MS [2]. However, no single variant alone can cause MS; rather, each one adds incrementally to the overall risk – a combined effect known as polygenicity [1]. Additionally, environmental and lifestyle factors interact with genetic predisposition, contributing to MS risk [1].
Gene discovery in different ancestral groups
GWAS have accounted for up to 48% of the genetic contribution to MS [3]. A total of 32 independent associations with MS susceptibility were identified within the major histocompatibility complex (MHC), 1 on the chromosome X, and 200 in the autosomal non-MHC genome [3]. The main genetic risk for MS was found in the human leukocyte antigen (HLA) region, with HLA-DRB1*15:01 being the most significant [4]. The HLA has been associated with the risk of MS since 1972 [5]. “Individuals carrying at least one copy of this allele have a risk of developing MS that is about three times higher compared to those without it”, Professor Vilija Jokubaitis from the Monash University tells us. Class II HLA alleles are linked to a higher risk of developing MS risk, while Class I HLA alleles are protective [5].
A study published in Nature last year revealed that the genetic risk for MS became increasingly common during the Bronze Age, around the time where steppe pastoralist populations migrated from Central Asia to Europe, approximately 5,000 years ago [4]. Pastoralist ancestry is associated to a positive selection pressure within the HLA region on chromosome 6, particularly in individuals of steppe ancestry [4]. These populations introduced direct contact with animals and their consumption in Europe, potentially exposing people to new pathogens. The increased pathogen pressure may have driven the positive selection of genetic variants, which are now associated to MS susceptibility [4].
Researchers are investigating also MS genetics in other ancestral groups. The genetic Association study in individuals from Diverse Ancestral backgrounds with MS (ADAMS) will continue for the next 10 years to gather genetic and phenotypic observations on individuals with MS from diverse ancestral backgrounds living in UK [6].
From gene discovery to functional genomics
Professor Jokubaitis says, “Many research groups have created a polygenic risk score to estimate a person’s genetic susceptibility to developing MS. This score is calculated by examining a person’s genome and giving weights to each of the 236 autosomal variants, based on how many risk alleles the person carries. The result is an overall weight of genetic risk score. Studies have shown that individuals with a family history of MS tend to have higher genetic risk scores than those without a family history. However, even family members who never develop MS can still have elevated genetic risk scores. So, in terms of predicting MS risk, we are not there yet.”
Genetic factors play a crucial yet complex role in MS. MS tends to run in families. Concordance rates are notably higher in monozygotic twins (20–30%) compared to dizygotic twins (2–5%) [7]. Professor Philip De Jager, from the Columbia University, tells us, “Ultimately, genetics likely represent only a minor component of the overall risk of developing MS. Genetic information can be a valuable tool for research purposes, as it is both easy to measure and highly precise. However, it is not yet accurate enough for use in practice. Therefore, we need to combine genetic data with other forms of information, such as dynamic markers that reflect exposure to various environmental and lifestyle risk factors.”
Environmental and lifestyle risk factors for MS include low vitamin D levels or insufficient sun (ultraviolet B) exposure, Epstein-Barr virus (EBV) infection, obesity, smoking, and gut health [8, 9] (see also our dedicated Spotlight). Some of these factors may not be linked to MS risk across all racial and ethnic groups [10].
“How exactly these factors come together is not clear. However, recently, the focus has shifted from gene discovery, which has been the main approach for about 15 years, to functional genomics – exploring which biological processes are altered by which genetic variants.”, Professor De Jager continues.
MS-associated genetic variants in the brain
Professor De Jager and his team derived a polygenic score for MS that was originally optimised for people of European ancestry but is informative for African American and Latino participants [2]. The team identified 76 genes affected by MS risk variants, performing a multi-ancestry genome-wide association study with more than 20,000 individuals with MS. The researchers looked at both the immune system and the central nervous system to explore the functional consequences of the genetic variants. T cells stood out as the most enriched cell type. However, the expression of IL7 and STAT3, was affected only in inhibitory neurons, which emerged as a key cell type in MS susceptibility [2].
“That was a big surprise for a number of reasons”, Professor De Jager comments, “First of all, until now, we had no evidence that a truly neuronal gene was being altered by MS-associated genetic variants. What is particularly unique is the role of inhibitory neurons, which are enriched for MS risk genes typically associated with T cell function. What I find especially fascinating is that IL7 and STAT3 — both classic immune genes, known for their roles in interleukin signaling — show altered expression specifically in inhibitory neurons. STAT3 is an important signaling molecule that controls a lot of immune response pathways and cell types. The fact that MS variants affect the expression of these immune-related genes within neurons, and not in T cells, is remarkable.
I think there is a lot more to discover in the brain. These findings challenge the long-standing view that MS originates solely from peripheral immune dysfunction attacking the brain. Instead, they point to an intricate interplay between the central nervous system and the peripheral immune system – a dynamic that may both trigger and drive the progression of MS within the brain.”
Genetics and progression
Important insights into the mechanisms determining progression are offered by the International Multiple Sclerosis Genetics Consortium and the MultipleMS Consortium, that identified a significant association with a specific variant – rs10191329 – with a significant clinical effect. Individuals with MS who carried this variant reached the point of needing a walking aid sooner – on average 3.7 years earlier [11]. In fact, rs10191329 is located between two genes – DYSF and ZNF638 – which are highly expressed in oligodendrocytes, the brain cells that are damaged in people with MS [11]. Similarly, research by the MSBase Genetics consortium demonstrated an enrichment of genetic variants associated with synaptic plasticity and oligodendroglial biology as associated with MS severity [12]. Both studies converged to show that vulnerability in CNS resilience regulates MS outcomes [13].
An environmental component to MS severity has previously been described. It is known, for example, that cigarette smoking can accelerate disease progression [14]. A gene-environment link in MS progression has been demonstrated by Professor Jokubaitis’ lab, which found distinct DNA methylation signals in genes related to neuronal structure and function in those with slow versus fast MS progression [15].
Genetics still has more to offer in understanding and managing MS. Future efforts should focus on diverse ethnic groups and on translating findings into clinical practice [13].
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Written by Stefania de Vito
Special thanks to Professor Philip De Jager (Columbia University, US) and to Professor Vilija Jokubaitis (Monash University, Australia) for their insights.
References
[1] Goris A et al. Lancet Neurol. 2022; 21(9): 830-842.
[2] De Jager P et al. preprint in Research Square 2025.
[3] International Multiple Sclerosis Genetics Consortium et al. Science 2019; 365.6460: eaav7188.
[4] Barrie W et al. Nature 2024; 625.7994: 321-328.
[5] Jokubaitis VG Mult. Scler. J. 2023; 29(3): 314-316.
[6] Jacobs BM et al. BMJ open 13.5 2023: e071656.
[7] Baranzini SE & Oksenberg JR TiG 2017; 33(12): 960-970.
[8] Dobson R & Giovannoni G. Eur. J. Neurol. 2019; 26(1): 27-40.
[9] Zhou X et al. Cell 2022; 185(19): 3467-3486.
[10] Schoeps VA et al. Mult. Scler. Relat. Dis. 2024; 81: 105375.
[11] Harroud A, Stridh P, McCauley JL, et al. Nature 2023; 619: 323–31.
[12] Jokubaitis VG et al. Brain 2023; 146. 2316-2331.
[13] Jokubaitis VG & Butzkueven H Lancet Neurol. 2023; 22(10): 879-881.
[14] Ramanujam R et al., JAMA Neurol. 2105; 72(10): 1117-1123
[15] Campagna MP et al Clinic. Epigen. 2022; 14(1): 194.