Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis

Anne Hinks; Joanna Cobb; Miranda C. Marion; Sampath Prahalad; Marc Sudman; John Bowes; Paul Martin; Mary E. Comeau; Satria Sajuthi; Robert Andrews; Milton Brown; Wei Min Chen; Patrick Concannon; Panos Deloukas; Sarah Edkins; Stephen Eyre; Patrick M. Gaffney; Stephen L. Guthery; Joel M. Guthridge; Sarah E. Hunt; Judith A. James; Mehdi Keddache; Kathy L. Moser; Peter A. Nigrovic; Suna Onengut-Gumuscu; Mitchell L. Onslow; Carlos D. Rosé; Stephen S. Rich; Kathryn J A Steel; Edward K. Wakeland; Carol A. Wallace; Lucy R. Wedderburn; Patricia Woo; John F. Bohnsack; Johannes Peter Haas; David N. Glass; Carl D. Langefeld; Wendy Thomson; Susan D. Thompson

doi:10.1038/ng.2614

Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis

Anne Hinks, Joanna Cobb, Miranda C. Marion, Sampath Prahalad, Marc Sudman, John Bowes, Paul Martin, Mary E. Comeau, Satria Sajuthi, Robert Andrews, Milton Brown, Wei Min Chen, Patrick Concannon, Panos Deloukas, Sarah Edkins, Stephen Eyre, Patrick M. Gaffney, Stephen L. Guthery, Joel M. Guthridge, Sarah E. HuntJudith A. James, Mehdi Keddache, Kathy L. Moser, Peter A. Nigrovic, Suna Onengut-Gumuscu, Mitchell L. Onslow, Carlos D. Rosé, Stephen S. Rich, Kathryn J A Steel, Edward K. Wakeland, Carol A. Wallace, Lucy R. Wedderburn, Patricia Woo, John F. Bohnsack, Johannes Peter Haas, David N. Glass, Carl D. Langefeld, Wendy Thomson, Susan D. Thompson

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Abstract

We used the Immunochip array to analyze 2,816 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor-negative polyarticular JIA), and 13,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 14 loci reaching genome-wide significance (P < 5 × 10^-8) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < 1 × 10^-6). Dense mapping of loci along with bioinformatics analysis refined the associations to one gene in each of eight regions, highlighting crucial pathways, including the interleukin (IL)-2 pathway, in JIA disease pathogenesis. The entire Immunochip content, the HLA region and the top 27 loci (P < 1 × 10^-6) explain an estimated 18, 13 and 6% of the risk of JIA, respectively. In summary, this is the largest collection of JIA cases investigated so far and provides new insight into the genetic basis of this childhood autoimmune disease.

Original language	English (US)
Pages (from-to)	664-669
Number of pages	6
Journal	Nature genetics
Volume	45
Issue number	6
DOIs	https://doi.org/10.1038/ng.2614
State	Published - Jun 2013

ASJC Scopus subject areas

Genetics

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Hinks, A., Cobb, J., Marion, M. C., Prahalad, S., Sudman, M., Bowes, J., Martin, P., Comeau, M. E., Sajuthi, S., Andrews, R., Brown, M., Chen, W. M., Concannon, P., Deloukas, P., Edkins, S., Eyre, S., Gaffney, P. M., Guthery, S. L., Guthridge, J. M., ... Thompson, S. D. (2013). Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nature genetics, 45(6), 664-669. https://doi.org/10.1038/ng.2614

Hinks, A, Cobb, J, Marion, MC, Prahalad, S, Sudman, M, Bowes, J, Martin, P, Comeau, ME, Sajuthi, S, Andrews, R, Brown, M, Chen, WM, Concannon, P, Deloukas, P, Edkins, S, Eyre, S, Gaffney, PM, Guthery, SL, Guthridge, JM, Hunt, SE, James, JA, Keddache, M, Moser, KL, Nigrovic, PA, Onengut-Gumuscu, S, Onslow, ML, Rosé, CD, Rich, SS, Steel, KJA, Wakeland, EK, Wallace, CA, Wedderburn, LR, Woo, P, Bohnsack, JF, Haas, JP, Glass, DN, Langefeld, CD, Thomson, W & Thompson, SD 2013, 'Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis', Nature genetics, vol. 45, no. 6, pp. 664-669. https://doi.org/10.1038/ng.2614

@article{c9b4c7fc51744e3d9b3e556d6780f0df,

title = "Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis",

abstract = "We used the Immunochip array to analyze 2,816 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor-negative polyarticular JIA), and 13,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 14 loci reaching genome-wide significance (P < 5 × 10-8) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < 1 × 10-6). Dense mapping of loci along with bioinformatics analysis refined the associations to one gene in each of eight regions, highlighting crucial pathways, including the interleukin (IL)-2 pathway, in JIA disease pathogenesis. The entire Immunochip content, the HLA region and the top 27 loci (P < 1 × 10-6) explain an estimated 18, 13 and 6% of the risk of JIA, respectively. In summary, this is the largest collection of JIA cases investigated so far and provides new insight into the genetic basis of this childhood autoimmune disease.",

author = "Anne Hinks and Joanna Cobb and Marion, {Miranda C.} and Sampath Prahalad and Marc Sudman and John Bowes and Paul Martin and Comeau, {Mary E.} and Satria Sajuthi and Robert Andrews and Milton Brown and Chen, {Wei Min} and Patrick Concannon and Panos Deloukas and Sarah Edkins and Stephen Eyre and Gaffney, {Patrick M.} and Guthery, {Stephen L.} and Guthridge, {Joel M.} and Hunt, {Sarah E.} and James, {Judith A.} and Mehdi Keddache and Moser, {Kathy L.} and Nigrovic, {Peter A.} and Suna Onengut-Gumuscu and Onslow, {Mitchell L.} and Ros{\'e}, {Carlos D.} and Rich, {Stephen S.} and Steel, {Kathryn J A} and Wakeland, {Edward K.} and Wallace, {Carol A.} and Wedderburn, {Lucy R.} and Patricia Woo and Bohnsack, {John F.} and Haas, {Johannes Peter} and Glass, {David N.} and Langefeld, {Carl D.} and Wendy Thomson and Thompson, {Susan D.}",

note = "Funding Information: We thank P. Gilbert for preparing UK JIA case samples for genotyping and M. Ryan for preparing US JIA case samples and the Cincinnati local control samples. Genotyping of the US JIA, German JIA and respective control collections was supported by US National Institutes of Health (NIH) grants RC1-AR-058587 and U01-AI-067150S1. In addition, subject recruitment and DNA preparation in the United States was largely funded by US NIH grants N01-AR-42272, P01-AR-048929 and P30-AR-473639, with contributions from the Arthritis Foundation, The Val A. Browning Charitable Foundation in Salt Lake City, Utah, and the Marcus Foundation, Inc., in Atlanta, Georgia, as well as US NIH grants K23-AR-50177 and R01-AR-060893. The Federal Ministry of Education and Research, Germany (BMBF grants 01GM0907 and 01 ZZ 0403) supported subject recruitment and sample preparation in Germany. Genotyping of the UK JIA case samples was supported by Arthritis Research UK (grant 17552). Sparks Childhood Arthritis Response to Medication Study was funded by Sparks, UK (08ICH09) and the Big Lottery Fund, UK (RG/1/010135231). The study is on the UK Medicines for Children Research Network (MCRN) portfolio. We acknowledge support from the Wake Forest School of Medicine Center for Public Health Genomics and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; R01-AR-057106) for computing resources and data analysis. Control sample recruitment and genotyping originating at the Oklahoma Medical Research Foundation (OMRF) was supported in part by NIH grants N01-AR-62277, P30-GM-103510, U19-AI-082714 and P30-AR-053483 from NIAMS, the National Institute of General Medicine Sciences (NIGMS) and the National Institute of Allergy and Infectious Diseases (NIAID). The contents are solely the responsibility of the authors and do not necessarily represent the official views of these institutes or the US NIH. We thank J. Barrett and C. Wallace for the SNP selection. We thank the Wellcome Trust Sanger Institute Genotyping Facility and, in particular, E. Gray, S. Bumpstead, D. Simpkin and H. Blackburn for typing the UK samples. We acknowledge use of DNA from the UK Blood Services collection of common controls (UKBS-CC collection), which is funded by Wellcome Trust grant 076113/C/04/Z and by a National Institute for Health Research program grant to National Health Service Blood and Transplant (RP-PG-0310-1002). We acknowledge the use of DNA from the British 1958 Birth Cohort Collection, which is funded by UK Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/01. Genotyping of control samples was supported, in part, by grants from Juvenile Diabetes Research Foundation International (JDRF) and the US NIH (U01 DK062418). We thank P.K. Gregersen at the Feinstein Institute for providing US control genotyping from the Genotype and Phenotype Registry supported by US NIH grant RC2AR059092. We thank the National Institute of Diabetes, Digestive and Kidney Diseases Inflammatory Bowel Disease (NIDDK IBD) Genetics Consortium for providing North American control genotyping supported by US NIH grants DK062431, DK062422, DK062420, DK062432, DK062423, DK062413 and DK062429. We gratefully acknowledge contributions from physicians at CCHMC and collaborating clinics. We also acknowledge the assistance of S. Kramer, B. Clifford and L. Ponder in subject recruitment and coordination of clinical information at Cincinnati Children{\textquoteright}s Hospital Medical Center, the University of Utah and Emory University, respectively. The Cincinnati normal control DNA collection was supported and made available by Cincinnati Children{\textquoteright}s Hospital Medical Center. Funding Information: The US controls were derived from 4 sources, including (i) 793 healthy children without known major health conditions recruited from the geographic area served by Cincinnati Children{\textquoteright}s Hospital Medical Center (CCHMC) and 119 healthy adults collected at CCHMC (previous JIA GWAS have included approximately 75% of only the pediatric controls); (ii) 484 healthy adult controls from Utah screened for autoimmune diseases (all were included in the replication cohorts of previous GWAS5,6); (iii) 848 healthy adult controls collected at the Oklahoma Medical Research Foundation; and (iv) 1,804 healthy US adult controls from the Genotype and Phenotype Registry and the NIDDK IBD Genetics Consortium. Healthy controls from the Oklahoma Medical Research Foundation (OMRF) were provided by the Lupus Family Registry and Repository (LFRR)39 and the Oklahoma Immune Cohort (OIC). Each individual completed the Connective Tissue Disease Screening Questionnaire (CSQ)40, and individuals with {\textquoteleft}probable{\textquoteright} systemic rheumatic disease were excluded. Each individual was enrolled into these studies after appropriate written consent and institutional review board (IRB) approval by the OMRF and the University of Oklahoma Health Sciences Center. Healthy controls were also provided from the University of Minnesota systemic lupus erythematosus (SLE) sibship collection41, and these subjects were enrolled after appropriate written consent and IRB approval by the University of Minnesota.",

year = "2013",

month = jun,

doi = "10.1038/ng.2614",

language = "English (US)",

volume = "45",

pages = "664--669",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

TY - JOUR

T1 - Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis

AU - Hinks, Anne

AU - Cobb, Joanna

AU - Marion, Miranda C.

AU - Prahalad, Sampath

AU - Sudman, Marc

AU - Bowes, John

AU - Martin, Paul

AU - Comeau, Mary E.

AU - Sajuthi, Satria

AU - Andrews, Robert

AU - Brown, Milton

AU - Chen, Wei Min

AU - Concannon, Patrick

AU - Deloukas, Panos

AU - Edkins, Sarah

AU - Eyre, Stephen

AU - Gaffney, Patrick M.

AU - Guthery, Stephen L.

AU - Guthridge, Joel M.

AU - Hunt, Sarah E.

AU - James, Judith A.

AU - Keddache, Mehdi

AU - Moser, Kathy L.

AU - Nigrovic, Peter A.

AU - Onengut-Gumuscu, Suna

AU - Onslow, Mitchell L.

AU - Rosé, Carlos D.

AU - Rich, Stephen S.

AU - Steel, Kathryn J A

AU - Wakeland, Edward K.

AU - Wallace, Carol A.

AU - Wedderburn, Lucy R.

AU - Woo, Patricia

AU - Bohnsack, John F.

AU - Haas, Johannes Peter

AU - Glass, David N.

AU - Langefeld, Carl D.

AU - Thomson, Wendy

AU - Thompson, Susan D.

N1 - Funding Information: We thank P. Gilbert for preparing UK JIA case samples for genotyping and M. Ryan for preparing US JIA case samples and the Cincinnati local control samples. Genotyping of the US JIA, German JIA and respective control collections was supported by US National Institutes of Health (NIH) grants RC1-AR-058587 and U01-AI-067150S1. In addition, subject recruitment and DNA preparation in the United States was largely funded by US NIH grants N01-AR-42272, P01-AR-048929 and P30-AR-473639, with contributions from the Arthritis Foundation, The Val A. Browning Charitable Foundation in Salt Lake City, Utah, and the Marcus Foundation, Inc., in Atlanta, Georgia, as well as US NIH grants K23-AR-50177 and R01-AR-060893. The Federal Ministry of Education and Research, Germany (BMBF grants 01GM0907 and 01 ZZ 0403) supported subject recruitment and sample preparation in Germany. Genotyping of the UK JIA case samples was supported by Arthritis Research UK (grant 17552). Sparks Childhood Arthritis Response to Medication Study was funded by Sparks, UK (08ICH09) and the Big Lottery Fund, UK (RG/1/010135231). The study is on the UK Medicines for Children Research Network (MCRN) portfolio. We acknowledge support from the Wake Forest School of Medicine Center for Public Health Genomics and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; R01-AR-057106) for computing resources and data analysis. Control sample recruitment and genotyping originating at the Oklahoma Medical Research Foundation (OMRF) was supported in part by NIH grants N01-AR-62277, P30-GM-103510, U19-AI-082714 and P30-AR-053483 from NIAMS, the National Institute of General Medicine Sciences (NIGMS) and the National Institute of Allergy and Infectious Diseases (NIAID). The contents are solely the responsibility of the authors and do not necessarily represent the official views of these institutes or the US NIH. We thank J. Barrett and C. Wallace for the SNP selection. We thank the Wellcome Trust Sanger Institute Genotyping Facility and, in particular, E. Gray, S. Bumpstead, D. Simpkin and H. Blackburn for typing the UK samples. We acknowledge use of DNA from the UK Blood Services collection of common controls (UKBS-CC collection), which is funded by Wellcome Trust grant 076113/C/04/Z and by a National Institute for Health Research program grant to National Health Service Blood and Transplant (RP-PG-0310-1002). We acknowledge the use of DNA from the British 1958 Birth Cohort Collection, which is funded by UK Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/01. Genotyping of control samples was supported, in part, by grants from Juvenile Diabetes Research Foundation International (JDRF) and the US NIH (U01 DK062418). We thank P.K. Gregersen at the Feinstein Institute for providing US control genotyping from the Genotype and Phenotype Registry supported by US NIH grant RC2AR059092. We thank the National Institute of Diabetes, Digestive and Kidney Diseases Inflammatory Bowel Disease (NIDDK IBD) Genetics Consortium for providing North American control genotyping supported by US NIH grants DK062431, DK062422, DK062420, DK062432, DK062423, DK062413 and DK062429. We gratefully acknowledge contributions from physicians at CCHMC and collaborating clinics. We also acknowledge the assistance of S. Kramer, B. Clifford and L. Ponder in subject recruitment and coordination of clinical information at Cincinnati Children’s Hospital Medical Center, the University of Utah and Emory University, respectively. The Cincinnati normal control DNA collection was supported and made available by Cincinnati Children’s Hospital Medical Center. Funding Information: The US controls were derived from 4 sources, including (i) 793 healthy children without known major health conditions recruited from the geographic area served by Cincinnati Children’s Hospital Medical Center (CCHMC) and 119 healthy adults collected at CCHMC (previous JIA GWAS have included approximately 75% of only the pediatric controls); (ii) 484 healthy adult controls from Utah screened for autoimmune diseases (all were included in the replication cohorts of previous GWAS5,6); (iii) 848 healthy adult controls collected at the Oklahoma Medical Research Foundation; and (iv) 1,804 healthy US adult controls from the Genotype and Phenotype Registry and the NIDDK IBD Genetics Consortium. Healthy controls from the Oklahoma Medical Research Foundation (OMRF) were provided by the Lupus Family Registry and Repository (LFRR)39 and the Oklahoma Immune Cohort (OIC). Each individual completed the Connective Tissue Disease Screening Questionnaire (CSQ)40, and individuals with ‘probable’ systemic rheumatic disease were excluded. Each individual was enrolled into these studies after appropriate written consent and institutional review board (IRB) approval by the OMRF and the University of Oklahoma Health Sciences Center. Healthy controls were also provided from the University of Minnesota systemic lupus erythematosus (SLE) sibship collection41, and these subjects were enrolled after appropriate written consent and IRB approval by the University of Minnesota.

PY - 2013/6

Y1 - 2013/6

N2 - We used the Immunochip array to analyze 2,816 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor-negative polyarticular JIA), and 13,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 14 loci reaching genome-wide significance (P < 5 × 10-8) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < 1 × 10-6). Dense mapping of loci along with bioinformatics analysis refined the associations to one gene in each of eight regions, highlighting crucial pathways, including the interleukin (IL)-2 pathway, in JIA disease pathogenesis. The entire Immunochip content, the HLA region and the top 27 loci (P < 1 × 10-6) explain an estimated 18, 13 and 6% of the risk of JIA, respectively. In summary, this is the largest collection of JIA cases investigated so far and provides new insight into the genetic basis of this childhood autoimmune disease.

AB - We used the Immunochip array to analyze 2,816 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor-negative polyarticular JIA), and 13,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 14 loci reaching genome-wide significance (P < 5 × 10-8) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < 1 × 10-6). Dense mapping of loci along with bioinformatics analysis refined the associations to one gene in each of eight regions, highlighting crucial pathways, including the interleukin (IL)-2 pathway, in JIA disease pathogenesis. The entire Immunochip content, the HLA region and the top 27 loci (P < 1 × 10-6) explain an estimated 18, 13 and 6% of the risk of JIA, respectively. In summary, this is the largest collection of JIA cases investigated so far and provides new insight into the genetic basis of this childhood autoimmune disease.

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U2 - 10.1038/ng.2614

DO - 10.1038/ng.2614

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AN - SCOPUS:84878739093

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SP - 664

EP - 669

JO - Nature genetics

JF - Nature genetics

IS - 6

ER -

Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis

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