Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis.

Area of Science:

• Genetics
• Neurology
• Immunology

Background:

• Rare genetic variants are increasingly recognized as significant contributors to the heritability of multiple sclerosis (MS).
• The role of rare variants in pediatric-onset multiple sclerosis (POMS) remains largely unexplored.

Purpose of the Study:

• To investigate the association between rare variants in genes linked to adult-onset MS risk and major histocompatibility complex (MHC) genes with POMS.
• To determine if rare genetic variants contribute to the susceptibility of POMS.

Main Methods:

• Analysis of DNA samples from 330 POMS cases and 306 controls using Illumina ExomeChip genotypes.
• Application of the gene-based "SKAT-O" method to test for associations between candidate genes and POMS risk.

Main Results:

• Significant associations were found between POMS and one adult-onset MS gene (PRF1) and two MHC genes (BRD2 and AGER) after multiple comparison correction.
• These associations appear independent of the known risk factor HLA-DRB1*1501.
• Rare minor alleles in PRF1 were more prevalent in POMS cases, while rare variants in BRD2 and AGER were more common in controls.

Conclusions:

• The findings support a role for rare coding variants in POMS susceptibility.
• Investigating rare genetic variations is crucial for understanding complex diseases like POMS, as these variants may be missed by common variant studies.