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 HanSwapan 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

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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<5×10?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
Article number204749
JournalAnnals of the Rheumatic Diseases
Issue number3
StatePublished - 1 Mar 2015


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