One of the major susceptibility loci identified for Systemic lupus erythematosus (SLE) lies within a common large inversion polymorphism region on chromosome 8p23. In this study, we further investigated the ‘extended’ 8p23 locus (~4 Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The study involved a North American discovery dataset (~1,200 subjects) and a replication dataset (>10,000 subjects) comprising European-descent individuals. Our results have implicated multiple (known+novel) SLE signals/genes at the extended 8p23 locus and suggested that this broad locus contributes to SLE risk through the effects of multiple genes/pathways. Our findings underline the importance of evaluating the entire inversion region for any disease/trait linked to this 8p23 locus. (http://jmg.bmj.com/content/early/2017/03/13/jmedgenet-2016-104247 )