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

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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.

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Figure 1: The ten pAID case cohorts and top pAID-association loci identified.
Figure 2: Pleiotropic loci with heterogeneous effect directions across pAIDs.
Figure 3: Integrated annotation of pAID-association loci using existing predictive and experimental data sets.
Figure 4: Tissue-specific gene set enrichment analysis (TGSEA) of pediatric and adult autoimmune data sets identifies autoimmune-associated gene expression patterns across immune cells and tissues.
Figure 5: Genetic variants shared across the ten pAIDs reveal autoimmune disease networks.

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Acknowledgements

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.

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Y.R.L. and H.H. were leading contributors in the design, analysis and writing of this study. D.J.A. contributed to data collection and literature review. B.F., Ø.F., L.A.D., S.D.T., M.L.B., S.L.G., A.L., E.P., E.R., C.S., A.S., E.M., M.S.S., B.A.L., M.P., R.K.R., D.C.W., H.C., C.C.-R., J.S.O., E.M.B., K.E.S., S.K., A.M.G., J. Snyder, T.H.F., C.P., R.N.B., J.E.M. and J.A.E. contributed samples and phenotypes. F.D.M., K.A.T., H.Q., R.M.C., C.E.K., F.W. and J. Satsangi provided assistance with samples, genotyping and data processing. S.D.Z., J.P.B., J.L. and H.L. contributed to, advised on and supervised statistical analysis. E.T.L.P., J.A.E. and B.J.K. assisted in composing and revising the manuscript. A.K., C.A.W., C.H., C.J.C., C.K., D.C., D.L., D.S.M., F.G., J.J.C., J.T.G., M.B., M.C.D., M.D.R., P.M.A.S., S.F.A.G., S.M.M., V.A., Y.G. and Z.W. read, edited and approved of the manuscript, along with all other authors.

Correspondence to Hakon Hakonarson.

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Li, Y., Li, J., Zhao, S. et al. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nat Med 21, 1018–1027 (2015) doi:10.1038/nm.3933

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