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

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

Ann. Rheum. Dis. 74 (3) e13 [2015-03-00; online 2014-02-14]

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. 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. 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. 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.

NGI Uppsala (SNP&SEQ Technology Platform) [Service]

National Genomics Infrastructure [Service]

PubMed 24532676

DOI 10.1136/annrheumdis-2013-204749

Crossref 10.1136/annrheumdis-2013-204749

pii: annrheumdis-2013-204749
pmc: PMC4467986
mid: NIHMS695249