High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci

Kwangwoo Kim, So Young Bang, Hye Soon Lee, Soo Kyung Cho, Chan Bum Choi, Yoon Kyoung Sung, Tae Hwan Kim, Jae Bum Jun, Dae Hyun Yoo, Young Mo Kang, Seong Kyu Kim, Chang Hee Suh, Seung Cheol Shim, Shin Seok Lee, Jisoo Lee, Won Tae Chung, Jung Yoon Choe, Hyoung Doo Shin, Jong Young Lee, Bok Ghee Han & 22 others Swapan K. Nath, Steve Eyre, John Bowes, Dimitrios A. Pappas, Joel M. Kremer, Miguel A. Gonzalez-Gay, Luis Rodriguez-Rodriguez, Lisbeth Ärlestig, Yukinori Okada, Dorothée Diogo, Katherine P. Liao, Elizabeth W. Karlson, Soumya Raychaudhuri, Solbritt Rantapää-Dahlqvist, Javier Martin, Lars Klareskog, Leonid Padyukov, Peter K. Gregersen, Jane Worthington, Jeffrey D. Greenberg, Robert M. Plenge, Sang Cheol Bae

Research output: Contribution to journalArticle

Abstract

Objective: A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods: We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45 790 European case-control samples. Results: We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p?8), with evidence for three independent risk alleles at 1q25/ TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusions: This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.

Original languageEnglish (US)
Article number204749
JournalAnnals of the Rheumatic Diseases
Volume74
Issue number3
DOIs
StatePublished - Mar 1 2015
Externally publishedYes

Fingerprint

Rheumatoid Arthritis
Alleles
Polymorphism
Single Nucleotide Polymorphism
Nucleotides
Genes
Genome-Wide Association Study
T-cells
Immune System Diseases
Sample Size
Autoimmune Diseases
Meta-Analysis
Genome
T-Lymphocytes
Peptides
Antibodies

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. / Kim, Kwangwoo; Bang, So Young; Lee, Hye Soon; Cho, Soo Kyung; Choi, Chan Bum; Sung, Yoon Kyoung; Kim, Tae Hwan; Jun, Jae Bum; Yoo, Dae Hyun; Kang, Young Mo; Kim, Seong Kyu; Suh, Chang Hee; Shim, Seung Cheol; Lee, Shin Seok; Lee, Jisoo; Chung, Won Tae; Choe, Jung Yoon; Shin, Hyoung Doo; Lee, Jong Young; Han, Bok Ghee; Nath, Swapan K.; Eyre, Steve; Bowes, John; Pappas, Dimitrios A.; Kremer, Joel M.; Gonzalez-Gay, Miguel A.; Rodriguez-Rodriguez, Luis; Ärlestig, Lisbeth; Okada, Yukinori; Diogo, Dorothée; Liao, Katherine P.; Karlson, Elizabeth W.; Raychaudhuri, Soumya; Rantapää-Dahlqvist, Solbritt; Martin, Javier; Klareskog, Lars; Padyukov, Leonid; Gregersen, Peter K.; Worthington, Jane; Greenberg, Jeffrey D.; Plenge, Robert M.; Bae, Sang Cheol.

In: Annals of the Rheumatic Diseases, Vol. 74, No. 3, 204749, 01.03.2015.

Research output: Contribution to journalArticle

Kim, K, Bang, SY, Lee, HS, Cho, SK, Choi, CB, Sung, YK, Kim, TH, Jun, JB, Yoo, DH, Kang, YM, Kim, SK, Suh, CH, Shim, SC, Lee, SS, Lee, J, Chung, WT, Choe, JY, Shin, HD, Lee, JY, Han, BG, Nath, SK, Eyre, S, Bowes, J, Pappas, DA, Kremer, JM, Gonzalez-Gay, MA, Rodriguez-Rodriguez, L, Ärlestig, L, Okada, Y, Diogo, D, Liao, KP, Karlson, EW, Raychaudhuri, S, Rantapää-Dahlqvist, S, Martin, J, Klareskog, L, Padyukov, L, Gregersen, PK, Worthington, J, Greenberg, JD, Plenge, RM & Bae, SC 2015, 'High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci', Annals of the Rheumatic Diseases, vol. 74, no. 3, 204749. https://doi.org/10.1136/annrheumdis-2013-204749
Kim, Kwangwoo ; Bang, So Young ; Lee, Hye Soon ; Cho, Soo Kyung ; Choi, Chan Bum ; Sung, Yoon Kyoung ; Kim, Tae Hwan ; Jun, Jae Bum ; Yoo, Dae Hyun ; Kang, Young Mo ; Kim, Seong Kyu ; Suh, Chang Hee ; Shim, Seung Cheol ; Lee, Shin Seok ; Lee, Jisoo ; Chung, Won Tae ; Choe, Jung Yoon ; Shin, Hyoung Doo ; Lee, Jong Young ; Han, Bok Ghee ; Nath, Swapan K. ; Eyre, Steve ; Bowes, John ; Pappas, Dimitrios A. ; Kremer, Joel M. ; Gonzalez-Gay, Miguel A. ; Rodriguez-Rodriguez, Luis ; Ärlestig, Lisbeth ; Okada, Yukinori ; Diogo, Dorothée ; Liao, Katherine P. ; Karlson, Elizabeth W. ; Raychaudhuri, Soumya ; Rantapää-Dahlqvist, Solbritt ; Martin, Javier ; Klareskog, Lars ; Padyukov, Leonid ; Gregersen, Peter K. ; Worthington, Jane ; Greenberg, Jeffrey D. ; Plenge, Robert M. ; Bae, Sang Cheol. / High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. In: Annals of the Rheumatic Diseases. 2015 ; Vol. 74, No. 3.
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abstract = "Objective: A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods: We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45 790 European case-control samples. Results: We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p?8), with evidence for three independent risk alleles at 1q25/ TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusions: This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.",
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T1 - High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci

AU - Kim, Kwangwoo

AU - Bang, So Young

AU - Lee, Hye Soon

AU - Cho, Soo Kyung

AU - Choi, Chan Bum

AU - Sung, Yoon Kyoung

AU - Kim, Tae Hwan

AU - Jun, Jae Bum

AU - Yoo, Dae Hyun

AU - Kang, Young Mo

AU - Kim, Seong Kyu

AU - Suh, Chang Hee

AU - Shim, Seung Cheol

AU - Lee, Shin Seok

AU - Lee, Jisoo

AU - Chung, Won Tae

AU - Choe, Jung Yoon

AU - Shin, Hyoung Doo

AU - Lee, Jong Young

AU - Han, Bok Ghee

AU - Nath, Swapan K.

AU - Eyre, Steve

AU - Bowes, John

AU - Pappas, Dimitrios A.

AU - Kremer, Joel M.

AU - Gonzalez-Gay, Miguel A.

AU - Rodriguez-Rodriguez, Luis

AU - Ärlestig, Lisbeth

AU - Okada, Yukinori

AU - Diogo, Dorothée

AU - Liao, Katherine P.

AU - Karlson, Elizabeth W.

AU - Raychaudhuri, Soumya

AU - Rantapää-Dahlqvist, Solbritt

AU - Martin, Javier

AU - Klareskog, Lars

AU - Padyukov, Leonid

AU - Gregersen, Peter K.

AU - Worthington, Jane

AU - Greenberg, Jeffrey D.

AU - Plenge, Robert M.

AU - Bae, Sang Cheol

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Objective: A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods: We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45 790 European case-control samples. Results: We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p?8), with evidence for three independent risk alleles at 1q25/ TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusions: This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.

AB - Objective: A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods: We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45 790 European case-control samples. Results: We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p?8), with evidence for three independent risk alleles at 1q25/ TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusions: This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.

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