TY - JOUR
T1 - Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases
AU - Li, Yun R.
AU - Li, Jin
AU - Zhao, Sihai D.
AU - Bradfield, Jonathan P.
AU - Mentch, Frank D.
AU - Maggadottir, S. Melkorka
AU - Hou, Cuiping
AU - Abrams, Debra J.
AU - Chang, Diana
AU - Gao, Feng
AU - Guo, Yiran
AU - Wei, Zhi
AU - Connolly, John J.
AU - Cardinale, Christopher J.
AU - Bakay, Marina
AU - Glessner, Joseph T.
AU - Li, Dong
AU - Kao, Charlly
AU - Thomas, Kelly A.
AU - Qiu, Haijun
AU - Chiavacci, Rosetta M.
AU - Kim, Cecilia E.
AU - Wang, Fengxiang
AU - Snyder, James
AU - Richie, Marylyn D.
AU - Flatø, Berit
AU - Førre, øystein
AU - Denson, Lee A.
AU - Thompson, Susan D.
AU - Becker, Mara L.
AU - Guthery, Stephen L.
AU - Latiano, Anna
AU - Perez, Elena
AU - Resnick, Elena
AU - Russell, Richard K.
AU - Wilson, David C.
AU - Silverberg, Mark S.
AU - Annese, Vito
AU - Lie, Benedicte A.
AU - Punaro, Marilynn
AU - Dubinsky, Marla C.
AU - Monos, Dimitri S.
AU - Strisciuglio, Caterina
AU - Staiano, Annamaria
AU - Miele, Erasmo
AU - Kugathasan, Subra
AU - Ellis, Justine A.
AU - Munro, Jane E.
AU - Sullivan, Kathleen E.
AU - Wise, Carol A.
AU - Chapel, Helen
AU - Cunningham-Rundles, Charlotte
AU - Grant, Struan F.A.
AU - Orange, Jordan S.
AU - Sleiman, Patrick M.A.
AU - Behrens, Edward M.
AU - Griffiths, Anne M.
AU - Satsangi, Jack
AU - Finkel, Terri H.
AU - Keinan, Alon
AU - Prak, Eline T.Luning
AU - Polychronakos, Constantin
AU - Baldassano, Robert N.
AU - Li, Hongzhe
AU - Keating, Brendan J.
AU - Hakonarson, Hakon
N1 - Funding Information:
We thank the subjects and their families for their participation in genotyping studies and the Biobank Repository at the Center for Applied Genomics at the Children’s Hospital of Philadelphia. We acknowledge M.V. Holmes, H. Matsunami, L. Steel and E. Carrigan for their technical assistance and review of the manuscript. We are also thankful for the contributions of the Italian IBD Group, including S. Cucchiara (Roma), P. Lionetti (Firenze), G. Barabino (Genova), G.L. de Angelis (Parma), G. Guariso (Padova), C. Catassi (Ancona), G. Lombardi (Pescara), A.M. Staiano (Napoli), D. De Venuto (Bari), C. Romano (Messina), R. D’incà (Padova), M. Vecchi (Milano), A. Andriulli and F. Bossa (S. Giovanni Rotondo). The data sets used for the replication analyses were obtained through dbGaP accession numbers phs000344, phs000127, phs000274, phs000171, phs000224, phs000130, phs000019, phs000091, phs000206, phs000168, phs000138, phs000125 and phs000092. We thank the NIH data repository, the investigators who contributed the phenotype data and DNA samples from their original studies, and the primary funding organizations that supported these contributing investigators. This study made use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http:// www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. 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.
Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/9/8
Y1 - 2015/9/8
N2 - 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.
AB - 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.
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U2 - 10.1038/nm.3933
DO - 10.1038/nm.3933
M3 - Article
C2 - 26301688
AN - SCOPUS:84941025159
SN - 1078-8956
VL - 21
SP - 1018
EP - 1027
JO - Nature Medicine
JF - Nature Medicine
IS - 9
ER -