High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.
Eyre S., Bowes J., Diogo D., Lee A., Barton A., Martin P., Zhernakova A., Stahl E., Viatte S., McAllister K., Amos CI., Padyukov L., Toes REM., Huizinga TWJ., Wijmenga C., Trynka G., Franke L., Westra H-J., Alfredsson L., Hu X., Sandor C., de Bakker PIW., Davila S., Khor CC., Heng KK., Andrews R., Edkins S., Hunt SE., Langford C., Symmons D., Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate None., Wellcome Trust Case Control Consortium None., Concannon P., Onengut-Gumuscu S., Rich SS., Deloukas P., Gonzalez-Gay MA., Rodriguez-Rodriguez L., Ärlsetig L., Martin J., Rantapää-Dahlqvist S., Plenge RM., Raychaudhuri S., Klareskog L., Gregersen PK., Worthington J.
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.