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

ABSTRACT: Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse ?(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.

SUBMITTER: Li YR

PROVIDER: S-EPMC4863040 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

Li Yun R YR Li Jin J Zhao Sihai D SD Bradfield Jonathan P JP Mentch Frank D FD Maggadottir S Melkorka SM Hou Cuiping C Abrams Debra J DJ Chang Diana D Gao Feng F Guo Yiran Y Wei Zhi Z Connolly John J JJ Cardinale Christopher J CJ Bakay Marina M Glessner Joseph T JT Li Dong D Kao Charlly C Thomas Kelly A KA Qiu Haijun H Chiavacci Rosetta M RM Kim Cecilia E CE Wang Fengxiang F Snyder James J Richie Marylyn D MD Flatø Berit B Førre Øystein Ø Denson Lee A LA Thompson Susan D SD Becker Mara L ML Guthery Stephen L SL Latiano Anna A Perez Elena E Resnick Elena E Russell Richard K RK Wilson David C DC Silverberg Mark S MS Annese Vito V Lie Benedicte A BA Punaro Marilynn M Dubinsky Marla C MC Monos Dimitri S DS Strisciuglio Caterina C Staiano Annamaria A Miele Erasmo E Kugathasan Subra S Ellis Justine A JA Munro Jane E JE Sullivan Kathleen E KE Wise Carol A CA Chapel Helen H Cunningham-Rundles Charlotte C Grant Struan F A SF Orange Jordan S JS Sleiman Patrick M A PM Behrens Edward M EM Griffiths Anne M AM Satsangi Jack J Finkel Terri H TH Keinan Alon A Prak Eline T Luning ET Polychronakos Constantin C Baldassano Robert N RN Li Hongzhe H Keating Brendan J BJ Hakonarson Hakon H

Nature medicine 20150824 9

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-as ...[more]

PMID: 26301688

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Dataset Information

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

Publications

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

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