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Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases

2015; Nature Portfolio; Volume: 21; Issue: 9 Linguagem: Inglês

10.1038/nm.3933

1546-170X

Leslie A. Lange, Jin Li, Sihai Dave Zhao, Jonathan P. Bradfield, Frank Mentch, Sólrún Melkorka Maggadóttir, Cuiping Hou, Debra Abrams, Diana Chang, Feng Gao, Yiran Guo, Zhi Wei, John J. Connolly, Christopher J. Cardinale, Marina Bakay, Joseph Glessner, Dong Li, Charlly Kao, Kelly Thomas, Haijun Qiu, Rosetta Chiavacci, Cecilia E Kim, Fengxiang Wang, James W. Snyder, Marylyn D Richie, Berit Flatø, Øystein Førre, Lee A. Denson, Susan D. Thompson, Mara L. Becker, Stephen L. Guthery, Anna Latiano, Elena Pérez, Elena S. Resnick, Richard K. Russell, David C. Wilson, Mark S. Silverberg, Vito Annese, Benedicte A. Lie, Marilynn Punaro, Marla C. Dubinsky, Dimitri Monos, Caterina Strisciuglio, Annamaria Staiano, Erasmo Miele, Subra Kugathasan, Justine A. Ellis, Jane Munro, Kathleen E. Sullivan, Carol A. Wise, Helen Chapel, Charlotte Cunningham‐Rundles, Struan F.A. Grant, Jordan S. Orange, Patrick Sleiman, Edward M. Behrens, Anne M. Griffiths, Jack Satsangi, Terri H. Finkel, Alon Keinan, Eline T. Luning Prak, Constantin Polychronakos, Robert N. Baldassano, Hongzhe Li, Brendan J. Keating, Hákon Hákonarson,

IL-33, ST2, and ILC Pathways

A meta-analysis across ten pediatric autoimmune diseases reveals shared genetic architecture and novel susceptibility loci. Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ2 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.