Multiple sclerosis risk variants influence the peripheral B-cell compartment early in life in the general population

Background and purpose Multiple sclerosis (MS) is associated with abnormal B-cell function, and MS genetic risk alleles affect multiple genes that are expressed in B cells. However, how these genetic variants impact the B-cell compartment in early childhood is unclear. In the current study, we aim to assess whether polygenic risk scores (PRSs) for MS are associated with changes in the blood B-cell compartment in children from the general population. Methods Six-year-old children from the population-based Generation R Study were included. Genotype data were used to calculate MS-PRSs and B-cell subset-enriched MS-PRSs, established by designating risk loci based on expression and function. Analyses of variance were performed to examine the effect of MS-PRSs on total B-cell numbers (n = 1261) as well as naive and memory subsets (n = 675). Results After correction for multiple testing, no significant associations were observed between MS-PRSs and total B-cell numbers and frequencies of subsets therein. A naive B-cell-MS-PRS (n = 26 variants) was significantly associated with lower relative, but not absolute, naive B-cell numbers (p = 1.03 x 10(-4) and p = 0.82, respectively), and higher frequencies and absolute numbers of CD27(+) memory B cells (p = 8.83 x 10(-4) and p = 4.89 x 10(-3), respectively). These associations remained significant after adjustment for Epstein-Barr virus seropositivity and the HLA-DRB1*15:01 genotype. Conclusions The composition of the blood B-cell compartment is associated with specific naive B-cell-associated MS risk variants during childhood, possibly contributing to MS pathophysiology later in life. Cell subset-specific PRSs may offer a more sensitive tool to define the impact of genetic risk on the immune system in diseases such as MS.

Automated summary

This study aimed to assess whether polygenic risk scores for MS are associated with changes in the blood B-cell compartment in children. The results showed that a naive B-cell-MS-PRS was significantly associated with lower naive B-cell numbers and higher frequencies and absolute numbers of memory B cells in children. The findings suggest that specific genetic risk variants may impact the composition of the blood B-cell compartment during childhood, potentially influencing MS pathophysiology later in life.