First Genome-Wide Analysis in Pediatric Multiple Sclerosis (MS) Confirms a Role for Adult MS Risk Variants and Reveals New Candidates (S29.001)

Objective: We conducted the first GWAS in pediatric MS and tested previously established adult MS-associated candidate genes for association. Background: Up to 10[percnt] of MS patients have symptoms before age 18 (i.e. pediatric-onset MS). Similar to adults, both genetic and environmental risk factors have been implicated. In addition to HLA-DRB1*15:01, results from GWAS in adults with MS have identified ~110 non-MHC MS variants. Methods: All subjects had whole genome profiles (Illumina or Affymetrix chips). Genotype imputation and very rigorous quality control criteria were applied. SHAPEIT2 for phasing was followed by IMPUTE2 (1000 Genomes Phase 3 integrated variant set, October, 2014). Each individual was characterized for genetic ancestry using MDS (PLINK) and STRUCTURE analysis; cases and controls were closely matched on genetic ancestry. Results: We assembled samples from 732 MS cases with onset <18 years (70[percnt] female, mean age of onset 13.9 (+/- 3.5) years, 46[percnt] non-white) and 27,187 controls for genetic studies. Results from whites-only analysis (394 cases, 10,875 controls) showed HLA-DRB1*1501 was strongly associated with MS (OR=2.62, 95[percnt] CI: 2.23-3.07, p=2.1x10-32). Further, 36 of 110 non-MHC SNPs (33[percnt]) were significant (p<0.05); rs2744148 (chr 16), rs3007421 (chr 1) and rs1800693 (chr 12) demonstrated strongest evidence of association with pediatric MS, with larger effects compared to adults: OR=2.94, 95[percnt] CI: 2.41-3.57, p=5.2 x10-27; OR=2.46, 95[percnt] CI: 2.02-2.98, p=3.0 x 10-19; and OR=1.74, 95[percnt] CI: 1.51-2.01, p=4.7 x 10-14, respectively. A weighted genetic risk score (wGRS, 110 variants) was strongly associated with pediatric MS (2.0 x 10-16). Results from GWAS showed at least three genomic regions harbored SNPs with p<10-7. Fine mapping and trans-ethnic meta-analyses are underway. Conclusions: Variants within genes involved in adult MS are also risk factors in children and suggest that similar biological processes are present in both groups. Genetic effects may be stronger in pediatric MS overall. Disclosure: Dr. Barcellos has nothing to disclose. Dr. Shao has nothing to disclose. Dr. Rhead has nothing to disclose. Dr. Gianfrancesco has nothing to disclose. Dr. Graves has nothing to disclose. Dr. Waldman has received royalty payments from UpToDate. Dr. Lotze has nothing to disclose. Dr. Schreiner has received personal compensation for activities with Biogen Idec and MSAA as a consultant. Dr. Belman has nothing to disclose. Dr. Greenberg has received personal compensation for activities with EMD Serono, Novartis, Amarantus, and MSAA for honoria and consulting. Dr. Greenberg has received personal compensation in an editorial capacity for JAMA Neurology. Dr. Greenberg has rece Dr. Weinstock-Guttman has received personal compensation for activities with Biogen Idec, Teva Neurosciences, EMD Serono, Pfizer, Novartis, Genzyme & Sanofi, Mylan, and Acorda. Dr. Aaen has nothing to disclose. Dr. Tillema has nothing to disclose. Dr. Hart has nothing to disclose. Dr. Ness has nothing to disclose. Dr. Harris has nothing to disclose. Dr. Rubin has nothing to disclose. Dr. Candee has nothing to disclose. Dr. Krupp has received licensing and/or royalty fees from Johnson and Johnson, AbbVie, and Grifols. Dr. Gorman has nothing to disclose. Dr. Benson has nothing to disclose. Dr. Rodriguez has received research support from Acorda Therapeutics, Inc. Dr. Chitnis has received personal compensation for activities with Novartis and Biogen. Dr. Chitnis has received research support from Merck-Serono and Novartis Pharmaceuticals. Dr. Mar has nothing to disclose. Dr. Vanderver has received research support from Shire Pharmaceuticals Group and Illumina. Dr. Kahn has nothing to disclose. Dr. Rose has received research support from Biogen Idec, AbbieVie Biotherapeutics, Teva, Cumming Foundation, National Multiple Sclerosis Society, VA and NIH. Dr. Roalstad has nothing to disclose. Dr. Casper has nothing to disclose. Dr. Shen has nothing to disclose. Dr. Quach has nothing to disclose. Dr. Metayer has nothing to disclose. Dr. Schaefer has nothing to disclose. Dr. Waubant has received personal compensation for activities with Roche Diagnostics Corporation, Genzyme Corporation, and Novartis. Dr. Waubant has received research support from Roche Diagnostics Corporation, Biogen Idec, and Novartis.