Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ2 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.
Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases / Li, Y. R.; Li, J.; Zhao, S. D.; Bradfield, J. P.; Mentch, F. D.; Maggadottir, S. M.; Hou, C.; Abrams, D. J.; Chang, D.; Gao, F.; Guo, Y.; Wei, Z.; Connolly, J. J.; Cardinale, C. J.; Bakay, M.; Glessner, J. T.; Li, D.; Kao, C.; Thomas, K. A.; Qiu, H.; Chiavacci, R. M.; Kim, C. E.; Wang, F.; Snyder, J.; Richie, M. D.; Flato, B.; Forre, O.; Denson, L. A.; Thompson, S. D.; Becker, M. L.; Guthery, S. L.; Latiano, A.; Perez, E.; Resnick, E.; Russell, R. K.; Wilson, D. C.; Silverberg, M. S.; Annese, V.; Lie, B. A.; Punaro, M.; Dubinsky, M. C.; Monos, D. S.; Strisciuglio, C.; Staiano, A.; Miele, E.; Kugathasan, S.; Ellis, J. A.; Munro, J. E.; Sullivan, K. E.; Wise, C. A.; Chapel, H.; Cunningham-Rundles, C.; Grant, S. F. A.; Orange, J. S.; Sleiman, P. M. A.; Behrens, E. M.; Griffiths, A. M.; Satsangi, J.; Finkel, T. H.; Keinan, A.; Prak, E. T. L.; Polychronakos, C.; Baldassano, R. N.; Li, H.; Keating, B. J.; Hakonarson, H.. - In: NATURE MEDICINE. - ISSN 1078-8956. - 21:9(2015), pp. 1018-1027. [10.1038/nm.3933]
Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases
Annese V.;
2015-01-01
Abstract
Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ2 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
