How Our DNA Shapes Multiple Sclerosis: The Genetic Fingerprints Hidden in Brain Lesions
Multiple sclerosis (MS) is a complex immune-mediated disease that attacks the brain and spinal cord, leading to demyelination — the loss of the protective myelin sheath surrounding nerve fibers. While the disease has been studied for decades, one of its greatest mysteries remains: why does it vary so much between individuals?
Some patients experience mild, intermittent relapses, while others face relentless progression and neurodegeneration. Environmental factors, infections, and immune dysfunction play important roles, but genetics also has a profound influence on how MS develops and evolves.
A study published in Brain Pathology by Nina L. Fransen, Inge Huitinga, and colleagues at the Netherlands Institute for Neuroscience takes a major step toward understanding this connection. Their work, titled “Post-mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms,” bridges the gap between genetic variation and the microscopic patterns of brain lesions seen in MS patients after death.
Connecting Genes to the Brain: A Unique Post-Mortem Approach
The research team examined brain tissue from 179 MS donors collected by the Netherlands Brain Bank. Each brain was meticulously analyzed to classify different lesion types — active, chronic active (mixed active/inactive), inactive, and remyelinated — reflecting various stages of inflammation and repair.
At the same time, the scientists genotyped the donors for 102 single nucleotide polymorphisms (SNPs), small genetic variations previously linked to MS risk, disease severity, or immune function. The goal was to determine whether certain genetic variants influence how MS lesions form, evolve, or repair themselves.
This study is among the first to combine large-scale genetic data with quantitative neuropathology, offering a rare window into how DNA differences shape disease processes at the cellular level.
Six Genetic Variants That Change the Face of MS Lesions
After extensive statistical analysis, six SNPs showed significant associations with different types of MS lesions. Each variant mapped to a gene with a plausible biological role in immunity or neural health:
FAS (rs2234978) — linked to a higher proportion of active lesions, suggesting increased cell death signaling.
KCNIP1 (rs11957313) — associated with fewer active lesions, possibly via neuronal regulation.
CLEC16A (rs8056098) — correlated with fewer chronic active lesions, consistent with milder disease.
MOG (rs3130253) — tied to more active lesions, implicating altered myelin antigen expression.
NCAN (rs1064395) — associated with more cortical gray matter lesions, reflecting neuronal vulnerability.
CTLA4 (rs5742909) — linked to more remyelinated lesions, hinting at enhanced repair.
Together, these findings illustrate that genetic variation not only determines who develops MS but also influences the pathological “style” of the disease — whether inflammation burns hot, smolders, or resolves with regeneration.
The FAS Variant: When Cell Death Becomes a Double-Edged Sword
Among the six variants, the FAS gene stood out as particularly impactful. FAS encodes a receptor that triggers apoptosis, or programmed cell death — a crucial process in immune regulation and tissue maintenance.
The researchers discovered that carriers of the T allele of rs2234978 had significantly higher levels of FAS expression in both oligodendrocytes (the myelin-producing cells of the brain) and T cells. These individuals also showed a greater proportion of active lesions, indicating more ongoing tissue destruction.
This suggests two possible mechanisms. First, elevated FAS expression in oligodendrocytes could make them more vulnerable to apoptosis, accelerating myelin loss. Second, higher FAS levels in T cells — particularly regulatory T cells (Tregs) — could disrupt immune balance, reducing immune suppression and promoting inflammation. In either case, the variant amplifies damage and inflammation within the MS brain.
Neurocan (NCAN): The Structural Gene Behind Cortical Vulnerability
Another striking discovery involved the NCAN gene, which encodes Neurocan, a protein crucial for maintaining the brain’s extracellular matrix and supporting neuronal networks. The A allele of rs1064395 was associated with a higher number of cortical gray matter lesions, areas of demyelination linked to cognitive decline and disease progression.
Neurocan abnormalities have also been implicated in psychiatric conditions like schizophrenia and bipolar disorder, hinting that this protein plays a broader role in neuronal stability. In MS, altered Neurocan expression could destabilize perineuronal nets — protective structures around neurons — making the cortex more susceptible to demyelination.
Immune Regulators: CTLA4 and CLEC16A Shape Inflammation and Repair
Two immune-related genes, CTLA4 and CLEC16A, showed intriguing effects on lesion activity.
The CTLA4 variant (rs5742909) correlated with a higher proportion of remyelinated lesions, suggesting that increased CTLA4 signaling — which suppresses T-cell activation — may create a more favorable environment for myelin repair. This aligns with CTLA4’s known role as an “immune brake” that prevents excessive inflammation.
Conversely, CLEC16A (rs8056098) was linked to fewer chronic active lesions, the smoldering type that often drives progression. CLEC16A is involved in autophagy and cellular homeostasis; its protective variant may enhance cell survival and limit ongoing inflammation.
From Genes to Mechanisms: Translating Genotype into Pathology
This study goes beyond correlation by integrating gene expression analysis and cellular localization to explore how genetic variants manifest biologically. For example, increased FAS mRNA and protein were directly confirmed in brain tissue, particularly in oligodendrocytes and T cells near lesions.
By combining molecular and histological evidence, Fransen and colleagues demonstrate that genetic information can be translated into concrete cellular mechanisms — a critical step toward precision medicine in MS.
Implications for Personalized Medicine in MS
The implications of this work are far-reaching. For years, genetic studies have identified hundreds of variants associated with MS risk, but understanding how they influence disease behavior remained elusive. This study changes that by linking DNA sequence to lesion biology — the physical footprint of disease within the brain.
In the future, integrating genetic profiles with advanced imaging techniques (such as 7T MRI for detecting “iron rim” lesions) could help clinicians predict disease progression more accurately. Moreover, therapies targeting apoptosis, immune checkpoints, or autophagy pathways might be tailored based on an individual’s genotype.
Conclusion: The Genetic Signature of MS Lesions
The study by Fransen et al. marks a turning point in MS research. It shows that the small variations in our DNA — single nucleotide polymorphisms — can determine how our brains respond to inflammation, injury, and repair.
By coupling post-mortem neuropathology with cutting-edge genomics, the researchers reveal a clear genetic influence on the microscopic architecture of MS lesions. These findings not only enhance our understanding of disease heterogeneity but also pave the way toward personalized prognostics and targeted therapies in multiple sclerosis.
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:
Fransen, N. L., Crusius, J. B., Smolders, J., Mizee, M. R., van Eden, C. G., Luchetti, S., ... & Huitinga, I. (2020). Post‐mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms. Brain Pathology, 30(1), 106-119.
