Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex trait characterised by the production of a range of auto-antibodies and a diverse set of clinical phenotypes. Currently, similar to 8% of the genetic contribution to SLE in Europeans is known, following publication of several moderate-sized genome-wide (GW) association studies, which identified loci with a strong effect (OR > 1.3). In order to identify additional genes contributing to SLE susceptibility, we conducted a replication study in a UK dataset (870 cases, 5,551 controls) of 23 variants that showed moderate-risk for lupus in previous studies. Association analysis in the UK dataset and subsequent meta-analysis with the published data identified five SLE susceptibility genes reaching genome-wide levels of significance (P-comb < 5 x 10(-8)): NCF2 (P-comb = 2.87 x 10(-11)), IKZF1 (P-comb = 2.33 x 10(-9)), IRF8 (P-comb = 1.24 x 10(-8)), IFIH1 (P-comb = 1.63 x 10(-8)), and TYK2 (P-comb = 3.88 x 10(-8)). Each of the five new loci identified here can be mapped into interferon signalling pathways, which are known to play a key role in the pathogenesis of SLE. These results increase the number of established susceptibility genes for lupus to similar to 30 and validate the importance of using large datasets to confirm associations of loci which moderately increase the risk for disease.