title: 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 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.
authors: 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.
authors: Yun R
authors: http://orcid.org/0000-0002-8077-4975
authors: YR
authors: Li
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Jin
authors: J
authors: Li
authors: Department of Biostatistics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Sihai D
authors: SD
authors: Zhao
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Jonathan P
authors: JP
authors: Bradfield
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Frank D
authors: FD
authors: Mentch
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: S Melkorka
authors: SM
authors: Maggadottir
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Cuiping
authors: C
authors: Hou
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Debra J
authors: DJ
authors: Abrams
authors: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.|Program in Computational Biology and Medicine, Cornell University, Ithaca, New York, USA.
authors: Diana
authors: D
authors: Chang
authors: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.
authors: Feng
authors: F
authors: Gao
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Yiran
authors: http://orcid.org/0000-0002-6549-8589
authors: Y
authors: Guo
authors: Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey, USA.
authors: Zhi
authors: Z
authors: Wei
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: John J
authors: JJ
authors: Connolly
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Christopher J
authors: CJ
authors: Cardinale
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Marina
authors: M
authors: Bakay
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Joseph T
authors: JT
authors: Glessner
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Dong
authors: D
authors: Li
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Charlly
authors: C
authors: Kao
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Kelly A
authors: http://orcid.org/0000-0002-9719-2664
authors: KA
authors: Thomas
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Haijun
authors: H
authors: Qiu
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Rosetta M
authors: RM
authors: Chiavacci
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Cecilia E
authors: CE
authors: Kim
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Fengxiang
authors: F
authors: Wang
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: James
authors: J
authors: Snyder
authors: Department of Biochemistry and Molecular Biology, Eberly College of Science, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, Pennsylvania, USA.
authors: Marylyn D
authors: MD
authors: Richie
authors: Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors: Berit
authors: B
authors: Flatø
authors: Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors: Øystein
authors: Ø
authors: Førre
authors: Division of Gastroenterology, The Center for Inflammatory Bowel Disease, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors: Lee A
authors: LA
authors: Denson
authors: Divison of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors: Susan D
authors: SD
authors: Thompson
authors: Division of Rheumatology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA.
authors: Mara L
authors: ML
authors: Becker
authors: Department of Pediatrics, University of Utah School of Medicine and Primary Children's Medical Center, Salt Lake City, Utah, USA.
authors: Stephen L
authors: SL
authors: Guthery
authors: Division of Gastroenterology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors: Anna
authors: A
authors: Latiano
authors: Division of Pediatric Allergy and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: Elena
authors: E
authors: Perez
authors: Institute of Immunology and Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
authors: Elena
authors: E
authors: Resnick
authors: Department of Paediatric Gastroenterology, Yorkhill Hospital for Sick Children, Glasgow, Scotland, UK.
authors: Richard K
authors: RK
authors: Russell
authors: Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, University of Edinburgh, Ediburgh, UK.
authors: David C
authors: DC
authors: Wilson
authors: Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario, Canada.
authors: Mark S
authors: MS
authors: Silverberg
authors: Unit of Gastroenterology, Department of Medical and Surgical Specialties, Careggi University Hospital, Florence, Italy.
authors: Vito
authors: V
authors: Annese
authors: Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors: Benedicte A
authors: BA
authors: Lie
authors: Department of Rheumatology, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.
authors: Marilynn
authors: M
authors: Punaro
authors: Department of Pediatrics, Pediatric IBD Center, Cedars Sinai Medical Center, Los Angeles, California, USA.
authors: Marla C
authors: MC
authors: Dubinsky
authors: Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Dimitri S
authors: DS
authors: Monos
authors: Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy.
authors: Caterina
authors: C
authors: Strisciuglio
authors: Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy.
authors: Annamaria
authors: A
authors: Staiano
authors: Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy.
authors: Erasmo
authors: E
authors: Miele
authors: Department of Pediatrics, Emory University School of Medicine and Children's Health Care of Atlanta, Atlanta, Georgia, USA.
authors: Subra
authors: S
authors: Kugathasan
authors: Genes, Environment and Complex Disease, Murdoch Children's Research Institute, Parkville, Victoria, Australia.|Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia.
authors: Justine A
authors: JA
authors: Ellis
authors: Pediatric Rheumatology Unit, Royal Children's Hospital, Parkville, Victoria, Australia.|Arthritis and Rheumatology Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors: Jane E
authors: JE
authors: Munro
authors: Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Kathleen E
authors: KE
authors: Sullivan
authors: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.
authors: Carol A
authors: CA
authors: Wise
authors: Department of Clinical Immunology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors: Helen
authors: H
authors: Chapel
authors: Institute of Immunology and Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
authors: Charlotte
authors: C
authors: Cunningham-Rundles
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Struan F A
authors: SF
authors: Grant
authors: Section of Immunology, Allergy, and Rheumatology, Department of Pediatric Medicine, Texas Children's Hospital, Houston, Texas, USA.
authors: Jordan S
authors: JS
authors: Orange
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Patrick M A
authors: PM
authors: Sleiman
authors: Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Edward M
authors: EM
authors: Behrens
authors: The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors: Anne M
authors: AM
authors: Griffiths
authors: Gastrointestinal Unit, Division of Medical Sciences, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, UK.
authors: Jack
authors: J
authors: Satsangi
authors: Department of Pediatrics, Nemours Children's Hospital, Orlando, Florida, USA.
authors: Terri H
authors: TH
authors: Finkel
authors: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.|Program in Computational Biology and Medicine, Cornell University, Ithaca, New York, USA.
authors: Alon
authors: A
authors: Keinan
authors: Department of Pathology and Lab Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Eline T Luning
authors: ET
authors: Prak
authors: Departments of Pediatrics and Human Genetics, McGill University Health Centre Research Institute, Montréal, Québec, Canada.
authors: Constantin
authors: C
authors: Polychronakos
authors: Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Division of Gastroenterology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Robert N
authors: RN
authors: Baldassano
authors: Department of Pathology and Lab Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Hongzhe
authors: H
authors: Li
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Brendan J
authors: BJ
authors: Keating
authors: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Hakon
authors: H
authors: Hakonarson
mesh_terms: D001327:Autoimmune Diseases / Q000209:etiology / Q000235:genetics*; D002648:Child; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012307:Risk Factors