PhD defence C.L. (Casper) de Mol

Below is a brief summary of the dissertation:

In this thesis, we investigated the relationship between genetic and environmental risk factors for multiple sclerosis (MS) and brain and immune parameters in children from the general population. We used data from the Generation R Study, including MRI data and immunological measurements.

In Chapter 2, we examined the prevalence of radiologically isolated syndrome (RIS) in childhood. We found a very low prevalence (0.02%), and the identified patient did not develop MS after five years of follow-up.

Chapters 3 and 4 focused on genetic MS risk, measured through polygenic risk scores (PRS), and their association with MRI outcomes. We observed a positive association between MS-PRS and fractional anisotropy (FA), possibly indicating early structural brain changes. Voxel-wise analyses showed that genetic risk was associated with FA changes in regions such as the corpus callosum.

In Chapter 5, we studied both genetic and environmental risk factors for MS, including exposure to smoking, vitamin D levels, and Epstein-Barr virus. High genetic risk for MS combined with household smoking exposure was associated with lower brain volumes during childhood.

In Chapter 6, we described the effect of MS-PRS on the T-cell compartment. An increased CD4+/CD8+ ratio, associated with MS-related genetic variants, was already observable in childhood.

Chapter 7 demonstrated that MS genetic risk variants also affect the B-cell compartment: a higher MS-PRS was associated with fewer naïve B cells and more memory B cells, consistent with findings in MS patients.

Our findings suggest that early immunological and structural brain changes related to MS risk factors may contribute to the development of MS later in life.