Genetic Risk for MS Linked to White Matter Changes in Brains of Children

A high genetic risk for multiple sclerosis (MS) is associated with structural alterations in white matter — brain regions composed mainly of nerve fibers — in childhood, findings from a large study show.

Brain volume, however, was not affected by genetic risk in the more than 2,000 children whose data were examined.

The study, “Polygenic Multiple Sclerosis Risk and Population‐Based Childhood Brain Imaging,” was published in Annals of Neurology.

The microstructure and volume of some brain regions are known to be altered in adults and adolescents with MS. To some extend, these changes seem to be related to the presence of genetic variants that predispose to the disease.

Because many genetic variants known to contribute to MS risk do so to a small degree, researchers usually combine their information in a polygenic risk score (PRS) to more effectively quantify a person’s risk of developing MS. But most studies omit variants thought likely to contribute substantially to disease risk but not yet proven to do so.

No studies have assessed whether polygenic risk scores affect neurodevelopment during childhood.

A team from Erasmus University Medical Center Rotterdam, the Netherlands, set out to determine if a polygenic risk score — examining up to 161,270 variants — was associated with changes in the brain’s structure and volume in pre-adolescent children. (A gene variant describes any change — benign or disease-causing — in the DNA sequences that compose a gene.)

Their analysis included data on 2,224 children in the Generation R Study, following people in an urban setting from birth to young adulthood to better understand environmental and genetic causes of normal and abnormal growth.

All those included were of European ancestry, ages 8 to 12, and had available DNA data. A total of 1,136 individuals had undergone brain magnetic resonance imaging (MRI) to examine brain volume, and 1,088 had undergone another form of MRI that assesses white matter’s microstructure.

Children assessed for brain volume were a median age of 9.95, and a median of 9.96 among whose microstructure was examined. Both groups had an even distribution of boys and girls.

Interestingly, the mothers of children who had data for any of the MRI analyses had a higher level of education than did those whose children went without imaging scans, the researchers noted.

Depending on how significantly variants were associated with MS, researchers calculated eight different polygenic scores for each child. The broader one included all 161,270 variants, regardless of a significant association with MS. The most stringent examined only 198 variants with the strongest association with MS.

Results showed no significant changes in brain volume, or in the volume of different brain regions. But an association was seen between a higher polygenic risk score and changes in the brain’s global microstructure.

This was true for most polygenic risk scores, although the strongest association was seen for a score that took into account 7,920 different variants. This score explained about 1% of the variance seen across patients.

Next, the team used this score to understand if it was also associated with microstructural changes in specific white matter tracts (specific bundles of nerve fibers). They found positive associations in several tracts, including the superior longitudinal fasciculus, the forceps minor, the cingulate gyrus part of the cingulum, and the corticospinal tract. But none remained significant after adjusting for changes in global white matter microstructure.

Similar findings were observed in another group of 186 children from the Generation R Study who were scanned at an earlier age (median of 8.5 years old).

Researchers also examined if the genetic risk for MS had any impact on nonverbal IQ in 2,060 children (mean age at IQ assessment, 6). While an association was first observed, it failed to reach statistical significance after adjusting for multiple factors.

These findings show “evidence for a relationship between the combination of common genetic variants for MS and brain imaging [findings],” the researchers wrote.

“We observed evidence that genetic risk for MS influences brain development, in particular the [white matter] microstructure, in a pediatric population at an early age,” they added, suggesting “a preadolescent time window within neurodevelopment in which MS risk variants act upon the brain.”