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

• Published in: Nature medicine Vol. 21; no. 9; pp. 1018 - 1027
• Main Authors: Li, Yun R, Li, Jin, Zhao, Sihai D, Bradfield, Jonathan P, Mentch, Frank D, Maggadottir, S Melkorka, Hou, Cuiping, Abrams, Debra J, Chang, Diana, Gao, Feng, Guo, Yiran, Wei, Zhi, Connolly, John J, Cardinale, Christopher J, Bakay, Marina, Glessner, Joseph T, Li, Dong, Kao, Charlly, Thomas, Kelly A, Qiu, Haijun, Chiavacci, Rosetta M, Kim, Cecilia E, Wang, Fengxiang, Snyder, James, Richie, Marylyn D, Flatø, Berit, Førre, Øystein, Denson, Lee A, Thompson, Susan D, Becker, Mara L, Guthery, Stephen L, Latiano, Anna, Perez, Elena, Resnick, Elena, Russell, Richard K, Wilson, David C, Silverberg, Mark S, Annese, Vito, Lie, Benedicte A, Punaro, Marilynn, Dubinsky, Marla C, Monos, Dimitri S, Strisciuglio, Caterina, Staiano, Annamaria, Miele, Erasmo, Kugathasan, Subra, Ellis, Justine A, Munro, Jane E, Sullivan, Kathleen E, Wise, Carol A, Chapel, Helen, Cunningham-Rundles, Charlotte, Grant, Struan F A, Orange, Jordan S, Sleiman, Patrick M A, Behrens, Edward M, Griffiths, Anne M, Satsangi, Jack, Finkel, Terri H, Keinan, Alon, Prak, Eline T Luning, Polychronakos, Constantin, Baldassano, Robert N, Li, Hongzhe, Keating, Brendan J, Hakonarson, Hakon
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2015; Nature Publishing Group
• Subjects: 13; 38; 38/22; 38/39; 38/77; 45/43; 45/61; 631/208/205/2138; 631/250/248; 64/60; 692/53/2423; 692/699/249/1313; Autoimmune diseases; Autoimmune Diseases - etiology; Autoimmune Diseases - genetics; Biomedicine; Cancer Research; Case studies; Child; Children; Diseases; Gene mapping; Genetics; Genome-Wide Association Study; Genomics; Humans; Hypersensitivity; Infectious Diseases; Meta-analysis; Metabolic Diseases; Molecular Medicine; Neurosciences; Pediatrics; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Risk Factors; Single nucleotide polymorphisms; Australia; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.3933

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 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 (T H 1, T H 2 and T H 17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.