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

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  • 02/20/2025
Type of Material
Authors
    Yun R. Li, Children's Hospital of PhiladelphiaJin Li, Children's Hospital of PhiladelphiaSihai D. Zhao, University of PennsylvaniaJonathan P. Bradfield, Children's Hospital of PhiladelphiaFrank D. Mentch, Children's Hospital of PhiladelphiaS Melkorka Maggadottir, Children's Hospital of PhiladelphiaCuiping Hou, Children's Hospital of PhiladelphiaDebra J. Abrams, Children's Hospital of PhiladelphiaDiana Chang, Cornell UniversityFeng Gao, Cornell UniversityYiran Guo, Children's Hospital of PhiladelphiaZhi Wei, New Jersey Institute of TechnologyJohn J. Connolly, Children's Hospital of PhiladelphiaChristopher J. Cardinale, Children's Hospital of PhiladelphiaMarina Bakay, Children's Hospital of PhiladelphiaJoseph T. Glessner, Children's Hospital of PhiladelphiaDong Li, Children's Hospital of PhiladelphiaCharlly Kao, Children's Hospital of PhiladelphiaKelly A. Thomas, Children's Hospital of PhiladelphiaHaijun Qiu, Children's Hospital of PhiladelphiaRosetta M. Chiavacci, Children's Hospital of PhiladelphiaCecilia E. Kim, Children's Hospital of PhiladelphiaFengxiang Wang, Children's Hospital of PhiladelphiaJames Snyder, Children's Hospital of PhiladelphiaMarylyn Richie, Pennsylvania State UniversityBerit Flatø, University of OsloØystein Førre, University of OsloLee A. Denson, Cincinnati Children’s Hospital Medical CenterSusan D. Thompson, Cincinnati Children’s Hospital Medical CenterMara L. Becker, Children’s Mercy Hospitals and ClinicsStephen L. Guthery, University of UtahAnna Latiano, IRCCS Casa Sollievo SofferenzaElena Perez, University of MiamiElena Resnick, Mount Sinai School of MedicineRichard K. Russell, Yorkhill Hospital for Sick ChildrenDavid C. Wilson, University of EdinburghMark S. Silverberg, University of TorontoVito Annese, Careggi University HospitalBenedicte A. Lie, University of OsloMarilynn Punaro, Texas Scottish Rite Hospital for ChildrenMarla C. Dubinsky, Cedars Sinai Medical CenterDimitri S. Monos, Children's Hospital of PhiladelphiaCaterina Strisciuglio, University of Naples Federico IIAnnamaria Staiano, University of Naples Federico IIErasmo Miele, University of Naples Federico IISubramaniam Kugathasan, Emory UniversityJustine A. Ellis, Murdoch Children’s Research InstituteJane E. Munro, Royal Children’s Hospital, AustraliaKathleen E. Sullivan, Children's Hospital of PhiladelphiaCarol A. Wise, Texas Scottish Rite Hospital for ChildrenHelen Chapel, University of OxfordCharlotte Cunningham-Rundles, Mount Sinai School of MedicineStruan F.A. Grant, Children's Hospital of PhiladelphiaJordan S. Orange, Texas Children’s HospitalPatrick M.A. Sleiman, Children's Hospital of PhiladelphiaEdward M. Behrens, University of PennsylvaniaAnne M. Griffiths, University of TorontoJack Satsangi, University of EdinburghTerri H. Finkel, Nemours Children’s HospitalAlon Keinan, Children's Hospital of PhiladelphiaEline T. Prak, University of PennsylvaniaConstantin Polychronakos, McGill UniversityRobert N. Baldassano, University of PennsylvaniaHongzhe Li, University of PennsylvaniaBrendan J. Keating, Children's Hospital of PhiladelphiaHakon Hakonarson, Children's Hospital of Philadelphia
Language
  • English
Date
  • 2015-09-01
Publisher
  • Nature Publishing Group
Publication Version
Copyright Statement
  • © 2015 Nature America, Inc. All rights reserved.
Final Published Version (URL)
Title of Journal or Parent Work
ISSN
  • 1078-8956
Volume
  • 21
Issue
  • 9
Start Page
  • 1018
End Page
  • +
Grant/Funding Information
  • Y.R.L. is supported by the Paul and Daisy Soros Fellowship for New Americans and the NIH F30 Individual NRSA Training Grant.
  • This study was supported by Institutional Development Funds from The Children’s Hospital of Philadelphia and by DP3DK085708, RC1AR058606, U01HG006830, the Crohn’s & Colitis Foundation of America, the Juvenile Diabetes Research Foundation, NIH grant CA127334 (to H.L. and S.D.Z.), the UK National Institutes of Healthcare Research (to H.C.) and a grant from the Lupus Research Institute (to E.T.L.P.).
  • This work was supported in part by the NIH (grant R01-HG006849 to A.K.).
  • F.G. is a Howard Hughes Medical Institute International Student Research fellow.
  • Funding for the project was provided by the Wellcome Trust under award 076113.
Supplemental Material (URL)
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.
Author Notes
Keywords
Research Categories
  • Health Sciences, Immunology
  • Biology, Cell
  • Biology, Genetics

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