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

Research output: Contribution to journalArticle

76 Citations (Scopus)

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<sup>2</sup> 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<inf>H</inf>1, T<inf>H</inf>2 and T<inf>H</inf>17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)1018-1027
Number of pages10
JournalNature Medicine
Volume21
Issue number9
DOIs
StatePublished - Sep 8 2015

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Pediatrics
Autoimmune Diseases
Meta-Analysis
Age of Onset
Genes
Protein Interaction Maps
Th17 Cells
Th2 Cells
Th1 Cells
Population Control
T-cells
Deoxyribonucleases
Quantitative Trait Loci
Genome-Wide Association Study
Interleukins
Polymorphism
MicroRNAs
Computer Simulation
Interferons
Single Nucleotide Polymorphism

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Li, Y. R., Li, J., Zhao, S. D., Bradfield, J. P., Mentch, F. D., Maggadottir, S. M., ... 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

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

In: Nature Medicine, Vol. 21, No. 9, 08.09.2015, p. 1018-1027.

Research output: Contribution to journalArticle

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
Li YR, Li J, Zhao SD, Bradfield JP, Mentch FD, Maggadottir SM et al. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nature Medicine. 2015 Sep 8;21(9):1018-1027. https://doi.org/10.1038/nm.3933
Li, Yun R. ; Li, Jin ; Zhao, Sihai D. ; Bradfield, Jonathan P. ; Mentch, Frank D. ; Maggadottir, S. Melkorka ; Hou, Cuiping ; Abrams, Debra J. ; Chang, Diana ; Gao, Feng ; Guo, Yiran ; Wei, Zhi ; Connolly, John J. ; Cardinale, Christopher J. ; Bakay, Marina ; Glessner, Joseph T. ; Li, Dong ; Kao, Charlly ; Thomas, Kelly A. ; Qiu, Haijun ; Chiavacci, Rosetta M. ; Kim, Cecilia E. ; Wang, Fengxiang ; Snyder, James ; Richie, Marylyn D. ; Flatø, Berit ; Førre, øystein ; Denson, Lee A. ; Thompson, Susan D. ; Becker, Mara L. ; Guthery, Stephen L. ; Latiano, Anna ; Perez, Elena ; Resnick, Elena ; Russell, Richard K. ; Wilson, David C. ; Silverberg, Mark S. ; Annese, Vito ; Lie, Benedicte A. ; Punaro, Marilynn ; Dubinsky, Marla C. ; Monos, Dimitri S. ; Strisciuglio, Caterina ; Staiano, Annamaria ; Miele, Erasmo ; Kugathasan, Subra ; Ellis, Justine A. ; Munro, Jane E. ; Sullivan, Kathleen E. ; Wise, Carol A. ; Chapel, Helen ; Cunningham-Rundles, Charlotte ; Grant, Struan F A ; Orange, Jordan S. ; Sleiman, Patrick M A ; Behrens, Edward M. ; Griffiths, Anne M. ; Satsangi, Jack ; Finkel, Terri H. ; Keinan, Alon ; Prak, Eline T Luning ; Polychronakos, Constantin ; Baldassano, Robert N. ; Li, Hongzhe ; Keating, Brendan J. ; Hakonarson, Hakon. / Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. In: Nature Medicine. 2015 ; Vol. 21, No. 9. pp. 1018-1027.
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