High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

Abstract

Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

Figure 1. Manhattan plot of association statistics highlighting all autosomal loci associated to rheumatoid arthritis in the study

P values of association to ACPA positive rheumatoid arthritis from the meta-analysis of the Immunochip and GWAS data are shown. Known and new rheumatoid arthritis associated loci are shown in red and black respectively. Three associated loci (identified by a *) only reach P<5×10⁻⁸ when ACPA positive and ACPA negative cases are included in the analysis. The dashed grey line indicates genome-wide significance (P=5×10⁻⁸).