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

被引：177

作者：

Li, Yun R. ^{[1
,2
]}

Li, Jin ^{[1
]}

Zhao, Sihai D. ^{[3
]}

Bradfield, Jonathan P. ^{[1
]}

Mentch, Frank D. ^{[1
]}

Maggadottir, S. Melkorka ^{[1
,4
]}

Hou, Cuiping ^{[1
]}

Abrams, Debra J. ^{[1
]}

Chang, Diana ^{[5
,6
]}

Gao, Feng ^{[5
]}

Guo, Yiran ^{[1
]}

Wei, Zhi ^{[7
]}

Connolly, John J. ^{[1
]}

Cardinale, Christopher J. ^{[1
]}

Bakay, Marina ^{[1
]}

Glessner, Joseph T. ^{[1
]}

Li, Dong ^{[1
]}

Kao, Charlly ^{[1
]}

Thomas, Kelly A. ^{[1
]}

Qiu, Haijun ^{[1
]}

Chiavacci, Rosetta M. ^{[1
]}

Kim, Cecilia E. ^{[1
]}

Wang, Fengxiang ^{[1
]}

Snyder, James ^{[1
]}

Richie, Marylyn D. ^{[8
]}

Flato, Berit ^{[9
]}

Forre, Oystein ^{[9
]}

Denson, Lee A. ^{[10
]}

Thompson, Susan D. ^{[11
]}

Becker, Mara L. ^{[12
]}

Guthery, Stephen L. ^{[13
,14
]}

Latiano, Anna ^{[15
]}

Perez, Elena ^{[16
]}

Resnick, Elena ^{[17
,18
]}

Russell, Richard K. ^{[19
]}

Wilson, David C. ^{[20
]}

Silverberg, Mark S. ^{[21
]}

Annese, Vito ^{[22
]}

Lie, Benedicte A. ^{[23
]}

Punaro, Marilynn ^{[24
]}

Dubinsky, Marla C. ^{[25
]}

Monos, Dimitri S. ^{[26
,27
]}

Strisciuglio, Caterina ^{[28
]}

Staiano, Annamaria ^{[28
]}

Miele, Erasmo ^{[28
]}

Kugathasan, Subra ^{[29
,30
]}

Ellis, Justine A. ^{[31
,32
]}

Munro, Jane E. ^{[33
,34
]}

Sullivan, Kathleen E. ^{[4
,27
]}

Wise, Carol A. ^{[35
]}

机构：

[1] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[2] Univ Penn, Perelman Sch Med, Med Scientist Training Program, Philadelphia, PA 19104 USA

[3] Univ Penn, Perelman Sch Med, Dept Biostat, Philadelphia, PA 19104 USA

[4] Childrens Hosp Philadelphia, Div Allergy & Immunol, Philadelphia, PA 19104 USA

[5] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY USA

[6] Cornell Univ, Program Computat Biol & Med, Ithaca, NY USA

[7] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA

[8] Penn State Univ, Huck Inst Life Sci, Eberly Coll Sci, Dept Biochem & Mol Biol, University Pk, PA 16802 USA

[9] Univ Oslo, Rikshosp, Oslo Univ Hosp, Dept Rheumatol, N-0027 Oslo, Norway

[10] Cincinnati Childrens Hosp Med Ctr, Ctr Inflammatory Bowel Dis, Div Gastroenterol, Cincinnati, OH 45229 USA

[11] Cincinnati Childrens Hosp Med Ctr, Div Rheumatol, Cincinnati, OH 45229 USA

[12] Childrens Mercy Hosp & Clin, Div Rheumatol, Kansas City, MO USA

[13] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA

[14] Primary Childrens Med Ctr, Salt Lake City, UT 84103 USA

[15] IRCCS Casa Sollievo Sofferenza, Div Gastroenterol, San Giovanni Rotondo, Italy

[16] Univ Miami, Miller Sch Med, Div Pediat Allergy & Immunol, Miami, FL 33136 USA

[17] Mt Sinai Sch Med, Inst Immunol, New York, NY USA

[18] Mt Sinai Sch Med, Dept Med, New York, NY USA

[19] Yorkhill Hosp Sick Children, Dept Paediat Gastroenterol, Glasgow, Lanark, Scotland

[20] Univ Edinburgh, Royal Hosp Sick Children, Paediat Gastroenterol & Nutr, Ediburgh, England

[21] Univ Toronto, Mt Sinai Hosp IBD Ctr, Toronto, ON, Canada

[22] Careggi Univ Hosp, Dept Med & Surg Specialties, Unit Gastroenterol, Florence, Italy

[23] Univ Oslo, Rikshosp, Oslo Univ Hosp, Dept Immunol, N-0027 Oslo, Norway

[24] Texas Scottish Rite Hosp Children, Dept Rheumatol, Dallas, TX 75219 USA

[25] Cedars Sinai Med Ctr, Pediat IBD Ctr, Dept Pediat, Los Angeles, CA 90048 USA

[26] Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA 19104 USA

[27] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA

[28] Univ Naples Federico II, Sect Pediat, Dept Translat Med Sci, Naples, Italy

[29] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA

[30] Childrens Hlth Care Atlanta, Atlanta, GA USA

[31] Murdoch Childrens Res Inst, Genes Environm & Complex Dis, Parkville, Vic, Australia

[32] Univ Melbourne, Dept Pediat, Parkville, Vic 3052, Australia

[33] Royal Childrens Hosp, Pediat Rheumatol Unit, Parkville, Vic 3052, Australia

[34] Murdoch Childrens Res Inst, Arthritis & Rheumatol Res, Parkville, Vic, Australia

[35] Texas Scottish Rite Hosp Children, Sarah M & Charles E Seay Ctr Musculoskeletal Res, Dallas, TX 75219 USA

[36] Univ Oxford, Nuffield Dept Med, Dept Clin Immunol, Oxford, England

[37] Texas Childrens Hosp, Dept Pediat Med, Sect Immunol Allergy & Rheumatol, Houston, TX 77030 USA

[38] Childrens Hosp Philadelphia, Div Rheumatol, Philadelphia, PA 19104 USA

[39] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada

[40] Univ Edinburgh, Sch Mol & Clin Med, Div Med Sci, Gastrointestinal Unit, Edinburgh, Midlothian, Scotland

[41] Nemours Childrens Hosp, Dept Pediat, Orlando, FL USA

[42] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[43] McGill Univ, Ctr Hlth, Res Inst, Dept Pediat, Montreal, PQ, Canada

[44] McGill Univ, Ctr Hlth, Res Inst, Dept Human Genet, Montreal, PQ, Canada

[45] Childrens Hosp Philadelphia, Div Gastroenterol, Philadelphia, PA 19104 USA

[46] Childrens Hosp Philadelphia, Div Pulm Med, Philadelphia, PA 19104 USA

来源：

NATURE MEDICINE | 2015年 / 21卷 / 09期

基金：

英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; JUVENILE IDIOPATHIC ARTHRITIS; ONSET ANKYLOSING-SPONDYLITIS; ELECTRONIC MEDICAL-RECORDS; RHEUMATOID-ARTHRITIS; SUSCEPTIBILITY LOCI; GENOTYPE IMPUTATION; CROHNS-DISEASE; RISK LOCI;

D O I：

10.1038/nm.3933

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse chi(2) 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(H)1, T(H)2 and T(H)17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.

引用

页码：1018 / +

页数：16

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