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 × 10-4 and p = 0.82, respectively), and higher frequencies and absolute numbers of CD27+ memory B cells (p = 8.83 × 10-4 and p = 4.89 × 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.

Genetic variants associated with longitudinal changes in brain structure across the lifespan.

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

T cell composition and polygenic multiple sclerosis risk: A population-based study in children.

BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS) have altered T cell function and composition. Common genetic risk variants for MS affect proteins that function in the immune system. It is currently unclear to what extent T cell composition is affected by genetic risk factors for MS, and how this may precede a possible disease onset. Here, we aim to assess whether an MS polygenic risk score (PRS) is associated with an altered T cell composition in a large cohort of children from the general population. METHODS: We included genotyped participants from the population-based Generation R study in whom immunophenotyping of blood T cells was performed at the age of 6 years. Analyses of variance were used to determine the impact of MS-PRSs on total T cell numbers (n = 1261), CD4+ and CD8+ lineages, and subsets therein (n= 675). In addition, T-cell-specific PRSs were constructed based on functional pathway data. RESULTS: The MS-PRS negatively correlated with CD8+ T cell frequencies (p = 2.92 × 10-3 ), which resulted in a positive association with CD4+ /CD8+ T cell ratios (p = 8.27 × 10-9 ). These associations were mainly driven by two of 195 genome-wide significant MS risk variants: the main genetic risk variant for MS, HLA-DRB1*15:01 and an HLA-B risk variant. We observed no significant associations for the T-cell-specific PRSs. CONCLUSIONS: Our results suggest that MS-associated genetic variants affect T cell composition during childhood in the general population.