{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Horton MK"],"funding":["National Institute of Neurological Disorders and Stroke","National Institute of Environmental Health Sciences","Wayne and Gladys Valley Foundation","National Multiple Sclerosis Society","NIA NIH HHS","NIAID NIH HHS","NIEHS NIH HHS","NINDS NIH HHS","Division of Intramural Research, National Institute of Allergy and Infectious Diseases","Ellison Medical Foundation","Robert Wood Johnson Foundation"],"pagination":["505-511"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10149552"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["29(4-5)"],"pubmed_abstract":["<h4>Background</h4>Rare 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.<h4>Objective</h4>To test whether genes harboring rare variants associated with adult-onset MS risk (<i>PRF1, PRKRA, NLRP8</i>, and <i>HDAC7</i>) and 52 major histocompatibility complex (MHC) genes are associated with POMS.<h4>Methods</h4>We 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.<h4>Results</h4>After correction for multiple comparisons, one adult-onset MS gene (<i>PRF1, p</i> = 2.70 × 10<sup>-3</sup>) and two MHC genes (<i>BRD2, p</i> <i>=</i> 5.89 × 10<sup>-5</sup> and <i>AGER, p</i> <i>=</i> 7.96 × 10<sup>-5</sup>) were significantly associated with POMS. Results suggest these are independent of <i>HLA-DRB1*1501.</i><h4>Conclusion</h4>Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within <i>PRF1</i> were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, <i>BRD2</i> and <i>AGER</i>. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases."],"journal":["Multiple sclerosis (Houndmills, Basingstoke, England)"],"pubmed_title":["Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis."],"pmcid":["PMC10149552"],"funding_grant_id":["RC2 AG036607","R01 NS049510","5F31NS108668","R01 NS071463","R01NS049510","R01NS071463","HC0165","R01ES017080","R01 AI076544","F31 NS108668","R01AI076544","R01 ES017080","RC2AG036607"],"pubmed_authors":["Aaen G","Rodriguez M","Rensel M","Quach HL","Graves JS","Quach DL","Waubant E","Hart J","Wheeler Y","Casper TC","Schreiner T","Tillema JM","Barcellos LF","Shim JE","Greenberg B","Schaefer C","Mar S","Krupp L","Weinstock-Guttman B","Horton MK","Waldman A","Wallace A","Chitnis T"],"additional_accession":[]},"is_claimable":false,"name":"Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis.","description":"<h4>Background</h4>Rare 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.<h4>Objective</h4>To test whether genes harboring rare variants associated with adult-onset MS risk (<i>PRF1, PRKRA, NLRP8</i>, and <i>HDAC7</i>) and 52 major histocompatibility complex (MHC) genes are associated with POMS.<h4>Methods</h4>We 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.<h4>Results</h4>After correction for multiple comparisons, one adult-onset MS gene (<i>PRF1, p</i> = 2.70 × 10<sup>-3</sup>) and two MHC genes (<i>BRD2, p</i> <i>=</i> 5.89 × 10<sup>-5</sup> and <i>AGER, p</i> <i>=</i> 7.96 × 10<sup>-5</sup>) were significantly associated with POMS. Results suggest these are independent of <i>HLA-DRB1*1501.</i><h4>Conclusion</h4>Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within <i>PRF1</i> were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, <i>BRD2</i> and <i>AGER</i>. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Apr","modification":"2026-04-08T15:55:01.211Z","creation":"2025-02-19T02:38:50.037Z"},"accession":"S-EPMC10149552","cross_references":{"pubmed":["36755464"],"doi":["10.1177/13524585221150736"]}}