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

Yun R. Li; Jin Li; Sihai D. Zhao; Jonathan P. Bradfield; Frank D. Mentch; S. Melkorka Maggadottir; Cuiping Hou; Debra J. Abrams; Diana Chang; Feng Gao; Yiran Guo; Zhi Wei; John J. Connolly; Christopher J. Cardinale; Marina Bakay; Joseph T. Glessner; Dong Li; Charlly Kao; Kelly A. Thomas; Haijun Qiu; Rosetta M. Chiavacci; Cecilia E. Kim; Fengxiang Wang; James Snyder; Marylyn D. Richie; Berit Flatø; øystein Førre; Lee A. Denson; Susan D. Thompson; Mara L. Becker; Stephen L. Guthery; Anna Latiano; Elena Perez; Elena Resnick; Richard K. Russell; David C. Wilson; Mark S. Silverberg; Vito Annese; Benedicte A. Lie; Marilynn Punaro; Marla C. Dubinsky; Dimitri S. Monos; Caterina Strisciuglio; Annamaria Staiano; Erasmo Miele; Subra Kugathasan; Justine A. Ellis; Jane E. Munro; Kathleen E. Sullivan; Carol A. Wise; Helen Chapel; Charlotte Cunningham-Rundles; Struan F.A. Grant; Jordan S. Orange; Patrick M.A. Sleiman; Edward M. Behrens; Anne M. Griffiths; Jack Satsangi; Terri H. Finkel; Alon Keinan; Eline T.Luning Prak; Constantin Polychronakos; Robert N. Baldassano; Hongzhe Li; Brendan J. Keating; Hakon Hakonarson

doi:10.1038/nm.3933

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

Yun R. Li, Jin Li, Sihai D. Zhao, Jonathan P. Bradfield, Frank D. Mentch, S. Melkorka Maggadottir, Cuiping Hou, Debra J. Abrams, Diana Chang, Feng Gao, Yiran Guo, Zhi Wei, John J. Connolly, Christopher J. Cardinale, Marina Bakay, Joseph T. Glessner, Dong Li, Charlly Kao, Kelly A. Thomas, Haijun QiuRosetta M. Chiavacci, Cecilia E. Kim, Fengxiang Wang, James Snyder, Marylyn D. Richie, Berit Flatø, øystein Førre, Lee A. Denson, Susan D. Thompson, Mara L. Becker, Stephen L. Guthery, Anna Latiano, Elena Perez, Elena Resnick, Richard K. Russell, David C. Wilson, Mark S. Silverberg, Vito Annese, Benedicte A. Lie, Marilynn Punaro, Marla C. Dubinsky, Dimitri S. Monos, Caterina Strisciuglio, Annamaria Staiano, Erasmo Miele, Subra Kugathasan, Justine A. Ellis, Jane E. Munro, Kathleen E. Sullivan, Carol A. Wise, Helen Chapel, Charlotte Cunningham-Rundles, Struan F.A. Grant, Jordan S. Orange, Patrick M.A. Sleiman, Edward M. Behrens, Anne M. Griffiths, Jack Satsangi, Terri H. Finkel, Alon Keinan, Eline T.Luning Prak, Constantin Polychronakos, Robert N. Baldassano, Hongzhe Li, Brendan J. Keating, Hakon Hakonarson

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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 (T_H1, T_H2 and T_H17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.

Original language	English (US)
Pages (from-to)	1018-1027
Number of pages	10
Journal	Nature Medicine
Volume	21
Issue number	9
DOIs	https://doi.org/10.1038/nm.3933
State	Published - Sep 8 2015

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

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10.1038/nm.3933

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Li, Y. R., Li, J., Zhao, S. D., Bradfield, J. P., Mentch, F. D., Maggadottir, S. M., Hou, C., Abrams, D. J., Chang, D., Gao, F., Guo, Y., Wei, Z., Connolly, J. J., Cardinale, C. J., Bakay, M., Glessner, J. T., Li, D., Kao, C., Thomas, K. A., ... Hakonarson, H. (2015). Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nature Medicine, 21(9), 1018-1027. https://doi.org/10.1038/nm.3933

@article{e290e774db7b45269cbed94adb0edffb,

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 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 = "Li, {Yun R.} and Jin Li and Zhao, {Sihai D.} and Bradfield, {Jonathan P.} and Mentch, {Frank D.} and Maggadottir, {S. Melkorka} and Cuiping Hou and Abrams, {Debra J.} and Diana Chang and Feng Gao and Yiran Guo and Zhi Wei and Connolly, {John J.} and Cardinale, {Christopher J.} and Marina Bakay and Glessner, {Joseph T.} and Dong Li and Charlly Kao and Thomas, {Kelly A.} and Haijun Qiu and Chiavacci, {Rosetta M.} and Kim, {Cecilia E.} and Fengxiang Wang and James Snyder and Richie, {Marylyn D.} and Berit Flat{\o} and {\o}ystein F{\o}rre and Denson, {Lee A.} and Thompson, {Susan D.} and Becker, {Mara L.} and Guthery, {Stephen L.} and Anna Latiano and Elena Perez and Elena Resnick and Russell, {Richard K.} and Wilson, {David C.} and Silverberg, {Mark S.} and Vito Annese and Lie, {Benedicte A.} and Marilynn Punaro and Dubinsky, {Marla C.} and Monos, {Dimitri S.} and Caterina Strisciuglio and Annamaria Staiano and Erasmo Miele and Subra Kugathasan and Ellis, {Justine A.} and Munro, {Jane E.} and Sullivan, {Kathleen E.} and Wise, {Carol A.} and Helen Chapel and Charlotte Cunningham-Rundles and Grant, {Struan F.A.} and Orange, {Jordan S.} and Sleiman, {Patrick M.A.} and Behrens, {Edward M.} and Griffiths, {Anne M.} and Jack Satsangi and Finkel, {Terri H.} and Alon Keinan and Prak, {Eline T.Luning} and Constantin Polychronakos and Baldassano, {Robert N.} and Hongzhe Li and Keating, {Brendan J.} and Hakon Hakonarson",

note = "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{\textquoteright}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{\textquoteright}inc{\`a} (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{\textquoteright}s Hospital of Philadelphia and by DP3DK085708, RC1AR058606, U01HG006830, the Crohn{\textquoteright}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: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",

year = "2015",

month = sep,

day = "8",

doi = "10.1038/nm.3933",

language = "English (US)",

volume = "21",

pages = "1018--1027",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "9",

}

Li, YR, Li, J, Zhao, SD, Bradfield, JP, Mentch, FD, Maggadottir, SM, Hou, C, Abrams, DJ, Chang, D, Gao, F, Guo, Y, Wei, Z, Connolly, JJ, Cardinale, CJ, Bakay, M, Glessner, JT, Li, D, Kao, C, Thomas, KA, Qiu, H, Chiavacci, RM, Kim, CE, Wang, F, Snyder, J, Richie, MD, Flatø, B, Førre, Ø, Denson, LA, Thompson, SD, Becker, ML, Guthery, SL, Latiano, A, Perez, E, Resnick, E, Russell, RK, Wilson, DC, Silverberg, MS, Annese, V, Lie, BA, Punaro, M, Dubinsky, MC, Monos, DS, Strisciuglio, C, Staiano, A, Miele, E, Kugathasan, S, Ellis, JA, Munro, JE, Sullivan, KE, Wise, CA, Chapel, H, Cunningham-Rundles, C, Grant, SFA, Orange, JS, Sleiman, PMA, Behrens, EM, Griffiths, AM, Satsangi, J, Finkel, TH, Keinan, A, Prak, ETL, Polychronakos, C, Baldassano, RN, Li, H, Keating, BJ & Hakonarson, H 2015, 'Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases', Nature Medicine, vol. 21, no. 9, pp. 1018-1027. https://doi.org/10.1038/nm.3933

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

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AN - SCOPUS:84941025159

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SP - 1018

EP - 1027

JO - Nature Medicine

JF - Nature Medicine

IS - 9

ER -

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

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