학술논문
Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis
Document Type
article
Author
Horton, Mary K; Shim, Joan E; Wallace, Amelia; Graves, Jennifer S; Aaen, Gregory; Greenberg, Benjamin; Mar, Soe; Wheeler, Yolanda; Weinstock-Guttman, Bianca; Waldman, Amy; Schreiner, Teri; Rodriguez, Moses; Tillema, Jan-Mendelt; Chitnis, Tanuja; Krupp, Lauren; Casper, T Charles; Rensel, Mary; Hart, Janace; Quach, Hong L; Quach, Diana L; Schaefer, Catherine; Waubant, Emmanuelle; Barcellos, Lisa F
Source
Multiple Sclerosis Journal. 29(4-5)
Subject
Language
Abstract
BackgroundRare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown.ObjectiveTo test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS.MethodsWe analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method "SKAT-O," we tested the association between candidate genes and POMS risk.ResultsAfter correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10-3) and two MHC genes (BRD2, p = 5.89 × 10-5 and AGER, p = 7.96 × 10-5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501.ConclusionFindings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.