Title |
Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases
|
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Published in |
Nature Medicine, August 2015
|
DOI | 10.1038/nm.3933 |
Pubmed ID | |
Authors |
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 Qiu, Rosetta 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 |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 19 | 19% |
United Kingdom | 8 | 8% |
Spain | 6 | 6% |
France | 3 | 3% |
South Africa | 2 | 2% |
Venezuela, Bolivarian Republic of | 2 | 2% |
Canada | 2 | 2% |
Norway | 1 | <1% |
Mexico | 1 | <1% |
Other | 9 | 9% |
Unknown | 48 | 48% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 53 | 52% |
Scientists | 37 | 37% |
Practitioners (doctors, other healthcare professionals) | 7 | 7% |
Science communicators (journalists, bloggers, editors) | 4 | 4% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 4 | 1% |
United Kingdom | 1 | <1% |
Finland | 1 | <1% |
Netherlands | 1 | <1% |
Unknown | 297 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 71 | 23% |
Student > Ph. D. Student | 51 | 17% |
Student > Bachelor | 30 | 10% |
Student > Master | 29 | 10% |
Professor | 18 | 6% |
Other | 54 | 18% |
Unknown | 51 | 17% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 85 | 28% |
Biochemistry, Genetics and Molecular Biology | 57 | 19% |
Agricultural and Biological Sciences | 49 | 16% |
Immunology and Microbiology | 20 | 7% |
Computer Science | 7 | 2% |
Other | 30 | 10% |
Unknown | 56 | 18% |