Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13

Susan D. Thompson, Miranda C. Marion, Marc Sudman, Mary Ryan, Monica Tsoras, Timothy D. Howard, Michael G. Barnes, Paula S. Ramos, Wendy Thomson, Anne Hinks, Johannes Peter Haas, Sampath Prahalad, John F. Bohnsack, Carol A. Wise, Marilynn Punaro, Carlos D. Rosé, Nicholas M. Pajewski, Michael Spigarelli, Mehdi Keddache, Michael Wagner & 2 others Carl D. Langefeld, David N. Glass

Research output: Contribution to journalArticle

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Abstract

Objective In a genome-wide association study of Caucasian patients with juvenile idiopathic arthritis (JIA), we have previously described findings limited to autoimmunity loci shared by JIA and other diseases. The present study was undertaken to identify novel JIA-predisposing loci using genome-wide approaches. Methods The discovery cohort consisted of Caucasian JIA cases (n = 814) and local controls (n = 658) genotyped on the Affymetrix Genome-Wide SNP 6.0 Array, along with 2,400 out-of-study controls. In a replication study, we genotyped 10 single-nucleotide polymorphisms (SNPs) in 1,744 cases and 7,010 controls from the US and Europe. Results Analysis within the discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011) (odds ratio [OR] 1.37, P = 1.88 × 10-6) and at 10q21 near JMJD1C (rs647989 [OR 1.59, P = 6.1 × 10-8], rs12411988 [OR 1.57, P = 1.16 × 10-7], and rs10995450 [OR 1.31, P = 6.74 × 10-5]). Meta-analysis provided further evidence of association for these 4 SNPs (P = 3.6 × 10-7 for rs4688011, P = 4.33 × 10-5 for rs6479891, P = 2.71 × 10-5 for rs12411988, and P = 5.39 × 10-5 for rs10995450). Gene expression data on 68 JIA cases and 23 local controls showed cis expression quantitative trait locus associations for C3orf1 SNP rs4688011 (P = 0.024 or P = 0.034, depending on the probe set) and JMJD1C SNPs rs6479891 and rs12411988 (P = 0.01 or P = 0.04, depending on the probe set and P = 0.008, respectively). Using a variance component liability model, it was estimated that common SNP variation accounts for approximately one-third of JIA susceptibility. Conclusion Genetic association results and correlated gene expression findings provide evidence of JIA association at 3q13 and suggest novel genes as plausible candidates in disease pathology.

Original languageEnglish (US)
Pages (from-to)2781-2791
Number of pages11
JournalArthritis and Rheumatism
Volume64
Issue number8
DOIs
StatePublished - Aug 2012

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Juvenile Arthritis
Genome-Wide Association Study
Single Nucleotide Polymorphism
Odds Ratio
Genome
Gene Expression
Quantitative Trait Loci
Autoimmunity
Meta-Analysis
Pathology
Genes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Thompson, S. D., Marion, M. C., Sudman, M., Ryan, M., Tsoras, M., Howard, T. D., ... Glass, D. N. (2012). Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13. Arthritis and Rheumatism, 64(8), 2781-2791. https://doi.org/10.1002/art.34429

Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13. / Thompson, Susan D.; Marion, Miranda C.; Sudman, Marc; Ryan, Mary; Tsoras, Monica; Howard, Timothy D.; Barnes, Michael G.; Ramos, Paula S.; Thomson, Wendy; Hinks, Anne; Haas, Johannes Peter; Prahalad, Sampath; Bohnsack, John F.; Wise, Carol A.; Punaro, Marilynn; Rosé, Carlos D.; Pajewski, Nicholas M.; Spigarelli, Michael; Keddache, Mehdi; Wagner, Michael; Langefeld, Carl D.; Glass, David N.

In: Arthritis and Rheumatism, Vol. 64, No. 8, 08.2012, p. 2781-2791.

Research output: Contribution to journalArticle

Thompson, SD, Marion, MC, Sudman, M, Ryan, M, Tsoras, M, Howard, TD, Barnes, MG, Ramos, PS, Thomson, W, Hinks, A, Haas, JP, Prahalad, S, Bohnsack, JF, Wise, CA, Punaro, M, Rosé, CD, Pajewski, NM, Spigarelli, M, Keddache, M, Wagner, M, Langefeld, CD & Glass, DN 2012, 'Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13', Arthritis and Rheumatism, vol. 64, no. 8, pp. 2781-2791. https://doi.org/10.1002/art.34429
Thompson, Susan D. ; Marion, Miranda C. ; Sudman, Marc ; Ryan, Mary ; Tsoras, Monica ; Howard, Timothy D. ; Barnes, Michael G. ; Ramos, Paula S. ; Thomson, Wendy ; Hinks, Anne ; Haas, Johannes Peter ; Prahalad, Sampath ; Bohnsack, John F. ; Wise, Carol A. ; Punaro, Marilynn ; Rosé, Carlos D. ; Pajewski, Nicholas M. ; Spigarelli, Michael ; Keddache, Mehdi ; Wagner, Michael ; Langefeld, Carl D. ; Glass, David N. / Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13. In: Arthritis and Rheumatism. 2012 ; Vol. 64, No. 8. pp. 2781-2791.
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title = "Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13",
abstract = "Objective In a genome-wide association study of Caucasian patients with juvenile idiopathic arthritis (JIA), we have previously described findings limited to autoimmunity loci shared by JIA and other diseases. The present study was undertaken to identify novel JIA-predisposing loci using genome-wide approaches. Methods The discovery cohort consisted of Caucasian JIA cases (n = 814) and local controls (n = 658) genotyped on the Affymetrix Genome-Wide SNP 6.0 Array, along with 2,400 out-of-study controls. In a replication study, we genotyped 10 single-nucleotide polymorphisms (SNPs) in 1,744 cases and 7,010 controls from the US and Europe. Results Analysis within the discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011) (odds ratio [OR] 1.37, P = 1.88 × 10-6) and at 10q21 near JMJD1C (rs647989 [OR 1.59, P = 6.1 × 10-8], rs12411988 [OR 1.57, P = 1.16 × 10-7], and rs10995450 [OR 1.31, P = 6.74 × 10-5]). Meta-analysis provided further evidence of association for these 4 SNPs (P = 3.6 × 10-7 for rs4688011, P = 4.33 × 10-5 for rs6479891, P = 2.71 × 10-5 for rs12411988, and P = 5.39 × 10-5 for rs10995450). Gene expression data on 68 JIA cases and 23 local controls showed cis expression quantitative trait locus associations for C3orf1 SNP rs4688011 (P = 0.024 or P = 0.034, depending on the probe set) and JMJD1C SNPs rs6479891 and rs12411988 (P = 0.01 or P = 0.04, depending on the probe set and P = 0.008, respectively). Using a variance component liability model, it was estimated that common SNP variation accounts for approximately one-third of JIA susceptibility. Conclusion Genetic association results and correlated gene expression findings provide evidence of JIA association at 3q13 and suggest novel genes as plausible candidates in disease pathology.",
author = "Thompson, {Susan D.} and Marion, {Miranda C.} and Marc Sudman and Mary Ryan and Monica Tsoras and Howard, {Timothy D.} and Barnes, {Michael G.} and Ramos, {Paula S.} and Wendy Thomson and Anne Hinks and Haas, {Johannes Peter} and Sampath Prahalad and Bohnsack, {John F.} and Wise, {Carol A.} and Marilynn Punaro and Ros{\'e}, {Carlos D.} and Pajewski, {Nicholas M.} and Michael Spigarelli and Mehdi Keddache and Michael Wagner and Langefeld, {Carl D.} and Glass, {David N.}",
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T1 - Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13

AU - Thompson, Susan D.

AU - Marion, Miranda C.

AU - Sudman, Marc

AU - Ryan, Mary

AU - Tsoras, Monica

AU - Howard, Timothy D.

AU - Barnes, Michael G.

AU - Ramos, Paula S.

AU - Thomson, Wendy

AU - Hinks, Anne

AU - Haas, Johannes Peter

AU - Prahalad, Sampath

AU - Bohnsack, John F.

AU - Wise, Carol A.

AU - Punaro, Marilynn

AU - Rosé, Carlos D.

AU - Pajewski, Nicholas M.

AU - Spigarelli, Michael

AU - Keddache, Mehdi

AU - Wagner, Michael

AU - Langefeld, Carl D.

AU - Glass, David N.

PY - 2012/8

Y1 - 2012/8

N2 - Objective In a genome-wide association study of Caucasian patients with juvenile idiopathic arthritis (JIA), we have previously described findings limited to autoimmunity loci shared by JIA and other diseases. The present study was undertaken to identify novel JIA-predisposing loci using genome-wide approaches. Methods The discovery cohort consisted of Caucasian JIA cases (n = 814) and local controls (n = 658) genotyped on the Affymetrix Genome-Wide SNP 6.0 Array, along with 2,400 out-of-study controls. In a replication study, we genotyped 10 single-nucleotide polymorphisms (SNPs) in 1,744 cases and 7,010 controls from the US and Europe. Results Analysis within the discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011) (odds ratio [OR] 1.37, P = 1.88 × 10-6) and at 10q21 near JMJD1C (rs647989 [OR 1.59, P = 6.1 × 10-8], rs12411988 [OR 1.57, P = 1.16 × 10-7], and rs10995450 [OR 1.31, P = 6.74 × 10-5]). Meta-analysis provided further evidence of association for these 4 SNPs (P = 3.6 × 10-7 for rs4688011, P = 4.33 × 10-5 for rs6479891, P = 2.71 × 10-5 for rs12411988, and P = 5.39 × 10-5 for rs10995450). Gene expression data on 68 JIA cases and 23 local controls showed cis expression quantitative trait locus associations for C3orf1 SNP rs4688011 (P = 0.024 or P = 0.034, depending on the probe set) and JMJD1C SNPs rs6479891 and rs12411988 (P = 0.01 or P = 0.04, depending on the probe set and P = 0.008, respectively). Using a variance component liability model, it was estimated that common SNP variation accounts for approximately one-third of JIA susceptibility. Conclusion Genetic association results and correlated gene expression findings provide evidence of JIA association at 3q13 and suggest novel genes as plausible candidates in disease pathology.

AB - Objective In a genome-wide association study of Caucasian patients with juvenile idiopathic arthritis (JIA), we have previously described findings limited to autoimmunity loci shared by JIA and other diseases. The present study was undertaken to identify novel JIA-predisposing loci using genome-wide approaches. Methods The discovery cohort consisted of Caucasian JIA cases (n = 814) and local controls (n = 658) genotyped on the Affymetrix Genome-Wide SNP 6.0 Array, along with 2,400 out-of-study controls. In a replication study, we genotyped 10 single-nucleotide polymorphisms (SNPs) in 1,744 cases and 7,010 controls from the US and Europe. Results Analysis within the discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011) (odds ratio [OR] 1.37, P = 1.88 × 10-6) and at 10q21 near JMJD1C (rs647989 [OR 1.59, P = 6.1 × 10-8], rs12411988 [OR 1.57, P = 1.16 × 10-7], and rs10995450 [OR 1.31, P = 6.74 × 10-5]). Meta-analysis provided further evidence of association for these 4 SNPs (P = 3.6 × 10-7 for rs4688011, P = 4.33 × 10-5 for rs6479891, P = 2.71 × 10-5 for rs12411988, and P = 5.39 × 10-5 for rs10995450). Gene expression data on 68 JIA cases and 23 local controls showed cis expression quantitative trait locus associations for C3orf1 SNP rs4688011 (P = 0.024 or P = 0.034, depending on the probe set) and JMJD1C SNPs rs6479891 and rs12411988 (P = 0.01 or P = 0.04, depending on the probe set and P = 0.008, respectively). Using a variance component liability model, it was estimated that common SNP variation accounts for approximately one-third of JIA susceptibility. Conclusion Genetic association results and correlated gene expression findings provide evidence of JIA association at 3q13 and suggest novel genes as plausible candidates in disease pathology.

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