Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.
Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.
Li, YR; Li, J; Zhao, SD; Bradfield, JP; Mentch, FD; Maggadottir, SM; Hou, C; Abrams, DJ; Chang, D; Gao, F; Guo, Y; Wei, Z; Connolly, JJ; Cardinale, CJ; Bakay, M; Glessner, JT; Li, D; Kao, C; Thomas, KA; Qiu, H; Chiavacci, RM; Kim, CE; Wang, F; Snyder, J; Richie, MD; Flatø, B; Førre, Ø; Denson, LA; Thompson, SD; Becker, ML; Guthery, SL; Latiano, A; Perez, E; Resnick, E; Russell, RK; Wilson, DC; Silverberg, MS; Annese, V; Lie, BA; Punaro, M; Dubinsky, MC; Monos, DS; Strisciuglio, C; Staiano, A; Miele, E; Kugathasan, S; Ellis, JA; Munro, JE; Sullivan, KE; Wise, CA; Chapel, H; Cunningham-Rundles, C; Grant, SFA; Orange, JS; Sleiman, PMA; Behrens, EM; Griffiths, AM; Satsangi, J; Finkel, TH; Keinan, A; Prak, ETL; Polychronakos, C; Baldassano, RN; Li, H; Keating, BJ; Hakonarson, H
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