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

Yun R Li, Jin Li, Sihai D Zhao, Jonathan P Bradfield, Frank D Mentch, S Melkorka Maggadottir, Cuiping Hou, Debra J Abrams, Diana Chang, Feng Gao, Yiran Guo, Zhi Wei, John J Connolly, Christopher J Cardinale, Marina Bakay, Joseph T Glessner, Dong Li, Charlly Kao, Kelly A Thomas, Haijun QiuRosetta M Chiavacci, Cecilia E Kim, Fengxiang Wang, James Snyder, Marylyn D Richie, Berit Flatø, Øystein Førre, Lee A Denson, Susan D Thompson, Mara L Becker, Stephen L Guthery, Anna Latiano, Elena Perez, Elena Resnick, Richard K Russell, David C Wilson, Mark S Silverberg, Vito Annese, Benedicte A Lie, Marilynn Punaro, Marla C Dubinsky, Dimitri S Monos, Caterina Strisciuglio, Annamaria Staiano, Erasmo Miele, Subra Kugathasan, Justine A Ellis, Jane E Munro, Kathleen E Sullivan, Carol A Wise, Helen Chapel, Charlotte Cunningham-Rundles, Struan F A Grant, Jordan S Orange, Patrick M A 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, Hakon Hakonarson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)1018-27
Number of pages10
JournalNature Medicine
Issue number9
Early online date24 Aug 2015
Publication statusPublished - Sept 2015


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