title: Genetic sharing and heritability of paediatric age of onset autoimmune diseases.
abstract: Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Yun R
authors.identifier: http://orcid.org/0000-0002-8077-4975
authors.initials: YR
authors.lastname: Li
authors.affiliation: Department of Statistics, University of Illinois at Urbana-Champaign, Champaign, Illinois 61820, USA.
authors.forename: Sihai D
authors.initials: SD
authors.lastname: Zhao
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bradfield
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Maede
authors.initials: M
authors.lastname: Mohebnasab
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Steel
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Kobie
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Abrams
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Mentch
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Yiran
authors.identifier: http://orcid.org/0000-0002-6549-8589
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey 07103, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Connolly
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Cardinale
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Bakay
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: S Melkorka
authors.initials: SM
authors.lastname: Maggadottir
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kelly A
authors.identifier: http://orcid.org/0000-0002-9719-2664
authors.initials: KA
authors.lastname: Thomas
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Haijun
authors.initials: H
authors.lastname: Qui
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Rosetta M
authors.initials: RM
authors.lastname: Chiavacci
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Cecilia E
authors.initials: CE
authors.lastname: Kim
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: James
authors.initials: J
authors.lastname: Snyder
authors.affiliation: Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Oslo 0372, Norway.
authors.forename: Berit
authors.initials: B
authors.lastname: Flatø
authors.affiliation: Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Oslo 0372, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Førre
authors.affiliation: Center for Inflammatory Bowel Disease, Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
authors.affiliation: Divison of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Thompson
authors.affiliation: Division of Rheumatology and Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy-Kansas City, Kansas City, Missouri 64108, USA.
authors.forename: Mara L
authors.initials: ML
authors.lastname: Becker
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine and Primary Children's Medical Center, Salt Lake City, Utah 84113, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Guthery
authors.affiliation: RCCS 'Casa Sollievo della Sofferenza', Division of Gastroenterology, San Giovanni Rotondo 71013, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Latiano
authors.affiliation: Division of Pediatric Allergy and Immunology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Perez
authors.affiliation: Institute of Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, New York 10029, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Resnick
authors.affiliation: Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II", Naples 80138, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Strisciuglio
authors.affiliation: Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II", Naples 80138, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Staiano
authors.affiliation: Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II", Naples 80138, Italy.
authors.forename: Erasmo
authors.initials: E
authors.lastname: Miele
authors.affiliation: IBD Centre, Mount Sinai Hospital, University of Toronto, 441-600 University Avenue, Toronto, Ontario, Canada M5G 1X5.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Silverberg
authors.affiliation: Department of Immunology, Oslo University Hospital, Rikshospitalet, 0027 Oslo 0372, Norway.
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.affiliation: Texas Scottish Rite Hospital for Children, Dallas, Texas 750219, USA.
authors.forename: Marilynn
authors.initials: M
authors.lastname: Punaro
authors.affiliation: Yorkhill Hospital for Sick Children, Glasgow G38SJ, Scotland.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Russell
authors.affiliation: Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh and Child Life and Health, University of Edinburgh, Edinburgh EH9 1UW, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wilson
authors.affiliation: Departments of Pediatrics and Common Disease Genetics, Cedars Sinai Medical Center, Los Angeles, California 90048, USA.
authors.forename: Marla C
authors.initials: MC
authors.lastname: Dubinsky
authors.affiliation: Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Dimitri S
authors.initials: DS
authors.lastname: Monos
authors.affiliation: Unit of Gastroenterology, Department of Medical and Surgical Specialties, Careggi University Hospital, Viale Pieraccini 18, Florence 50139, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Annese
authors.affiliation: Paediatric Rheumatology Unit, Royal Children's Hospital, Parkville, Victoria 3052, Australia.|Arthritis and Rheumatology Research, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Munro
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas 750219, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Wise
authors.affiliation: Department of Clinical Immunology, Nuffield Department of Medicine, University of Oxford, OX1 1NF, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Chapel
authors.affiliation: Institute of Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, New York 10029, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
authors.affiliation: Section of Immunology, Allergy, and Rheumatology, Department of Pediatric Medicine, Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.affiliation: Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Division of Rheumatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Behrens
authors.affiliation: Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Sullivan
authors.affiliation: Department of Pediatrics, Emory University School of Medicine and Children's Health Care of Atlanta, Atlanta, Georgia 30329, USA.
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
authors.affiliation: Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Griffiths
authors.affiliation: Gastrointestinal Unit, Division of Medical Sciences, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Satsangi
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Struan F A
authors.initials: SFA
authors.lastname: Grant
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Patrick M A
authors.initials: PMA
authors.lastname: Sleiman
authors.affiliation: Department of Pediatrics, Nemours Children's Hospital, Orlando, Florida 32827, USA.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Finkel
authors.affiliation: Departments of Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada H3H 1P3.
authors.forename: Constantin
authors.initials: C
authors.lastname: Polychronakos
authors.affiliation: Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Division of Gastroenterology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Baldassano
authors.affiliation: Department of Pathology and Lab Medicine, Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Eline T
authors.initials: ET
authors.lastname: Luning Prak
authors.affiliation: Genes, Environment and Complex Disease, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.|Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Justine A
authors.initials: JA
authors.lastname: Ellis
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Hongzhe
authors.initials: H
authors.lastname: Li
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001327:Autoimmune Diseases / Q000151:congenital* / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics