6. Research into the genetic and hereditary aspects of MS and remyelination.
Multiple sclerosis (MS) is a disease in which many different genetic factors play a role. Instead of a single cause, hundreds of small genetic variations each contribute a little to the risk of developing MS. Many of these variants are active in immune cells, such as T and B cells, but also in brain cells like
At the Holtman lab at UMC Groningen, we aim to better understand this complexity. In the Netherlands Neurogenomics Database (NND) project, we combine unique data from the Netherlands Brain Bank, including clinical information, genetic data, and brain tissue from MS patients. By analyzing these data together, we have identified three distinct disease processes within MS (de Boer et al., Acta Neuropathologica, 2024). One of these processes may be linked to genetic factors.
In addition, together with Karim Kreft (University of Nottingham), we have identified three genetic subtypes of MS that differ in disease progression and symptoms (Kreft et al., Journal of Neurology, Neurosurgery & Psychiatry, 2026). One of these subtypes has a more severe course and responds less well to medication. This helps us better understand why treatments are not equally effective for everyone.
Work is also being done in the Jonker lab to better understand the genetics of MS. They have developed a technique called MPRA (Massively Parallel Reporter Assay), which can be used to determine which genetic variants actually influence cell type–specific gene activity. This helps bridge the gap between genetic risk factors and understanding their functional effects in cells.
Together, these studies contribute to a better understanding of MS and represent an important step toward more personalized diagnosis and treatment.
Projects
The role of genetic code on MS disease trajectories
RESEARCHERS – Inge R. Holtman, Bart Eggen, Erik Boddeke, Inge Huitinga
PROJECT: Multiple sclerosis (MS) is highly variable in how it manifests and progresses. Two people with MS at similar early stages can experience very different disease courses, while two others at different early stages may follow similar trajectories. At present, we do not fully understand this diversity, making it difficult to predict how the disease will progress for an individual patient.
Currently, around two hundred locations in the genome have been identified that influence the risk of developing MS. However, it is largely unknown how these genetic loci affect susceptibility to MS and its disease course. To better understand how an individual’s genetic code affects the brain, we have developed a research plan for ‘the Netherlands Neurogenomics Database’ in collaboration with the Netherlands Brain Bank (NBB).
In this project, we combine clinical parameters, neuropathological information, and genetic background from a large number of donors with various brain diseases, including MS. Using this database, we investigate the molecular and genetic mechanisms underlying MS to understand the sources of disease course variability and, ultimately, to improve prediction.
Donors to the NBB are incredibly important and enable us to carry out this research. They are the true heroes of this and many other projects!
Genetic predisposition in MS explained: Searching for the key genes for MS in the cells that matter
RESEARCHERS – Aaron Daniel Ramirez-Sanches, Iris Jonkers, Karim Kreft, Jan Meilof
PROJECT: MS is largely influenced by our hereditary/genetic material (
In this project, we will examine the building blocks within these regions and investigate what problems these altered building blocks cause in the cells and organs crucial for MS: the immune system and the cells of the brain and spinal cord. We will do this using a new method called SuRE-SNP. SuRE-SNP can determine which specific DNA building blocks are important in different cell types, including immune and brain cells. This reveals the mechanisms affected by these building blocks, allowing us to determine with much greater precision their consequences and how they contribute to the development of MS.
Using existing genetic data from a large group of people, we will identify all genes involved in MS disease processes and test their role in the functioning of key cells. In this way, we can map the effects of the genetic building blocks important for MS with unprecedented precision and identify new strategies to treat the disease.
Financial contribution from Stichting MS Research (19-1060)
Bridge between imaging phenotypes & genomics in precision medicine
RESEARCHERS – Shivam Kumar, Inge Holtman
This project is supported by a Chan Zuckerberg Initiative grant awarded to the Holtman lab in collaboration with the Netherlands Brain Bank for the Netherlands Neurogenomics Database.
EBV and genetic predisposition contribute to the development of MS
RESEARCHERS: Peer Wubbolts (MSCNN), Iris Jonkers (MSCNN), M.M. van Luijn (ErasMS)
Financial contribution from Stichting MS Research (23-1205)
