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
The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nat Med. 2015 Sep;21(9):1018-27. doi: 10.1038/nm.3933. Epub 2015 Aug 24.
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.
全基因组关联研究（GWAS）已鉴定出数百个易感基因，包括临床特征不同的自身免疫性疾病之间的共同关联。在一项病例对照研究中，我们对十种儿童期发病的自身免疫性疾病（pAID）进行了逆χ²荟萃分析，该研究纳入了超过6035例病例和10718例基于人群的共享对照。我们鉴定出27个全基因组显著位点，这些位点与一种或多种pAID相关，映射到计算机模拟复制的自身免疫相关基因（包括IL2RA）以及具有既定免疫调节功能的新候选位点，如ADGRL2、TENM3、ANKRD30A、ADCY7和CD40LG。与pAID相关的单核苷酸多态性（SNP）在脱氧核糖核酸酶（DNase）超敏位点、表达数量性状位点（eQTL）、微小RNA（miRNA）结合位点和编码变异方面功能富集。我们还基于免疫细胞表达谱鉴定出生物学相关的、与pAID相关的候选基因集，并发现了基因共享的证据。网络和蛋白质相互作用分析表明，1型、2型和17型辅助性T细胞（TH1、TH2和TH17）、JAK-STAT、干扰素和白细胞介素的信号通路在多种自身免疫性疾病中具有汇聚作用。
