Meta-analysis of shared genetic architecture across ten pediatric 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.
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.