Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type I interferon signature 1. Here we report a missense variant (g. 74779296G> A; p. Arg90His) in NCF1, encoding the p47 phox subunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by the Immunochip in the GTF2IRD1–GTF2I region at 7q11. 23 with a complex genomic structure. We show that the p. Arg90His substitution, which is reported to cause reduced reactive oxygen species (ROS) production 2, predisposes to SLE (odds ratio (OR)= 3.47 in Asians (P meta= 3.1× 10− 104), OR= 2.61 in European Americans, OR= 2.02 in African Americans) and other autoimmune diseases, including primary Sjögren's syndrome (OR= 2.45 in Chinese, OR= 2.35 in European Americans) and rheumatoid arthritis (OR= 1.65 in Koreans). Additionally, decreased and increased copy numbers of NCF1 predispose to and protect against SLE, respectively. Our data highlight the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases.