Using known interacting sets of transcription factors, we identified related disease-associated variants in the recognition sequences of a central target factor and its interacting partners (Figs. 3B, S11, S12) for factors involved in autoimmune disease, cancer and neurological development. IRF9 is a transcription factor associated with type I interferon induction (23). Of 26 transcription factors in the IRF9-centered interaction network, 15 represent transcription factors with recognition sequences in multiple distinct DHSs that contain GWAS variants associated with a wide variety of autoimmune disorders (P < 1.6×10-13, binomial; 2.8-fold enrichment vs. random SNPs, Fig. 3B) (12). Notably, 24.4% (64/262) of GWAS SNPs within DHSs of immune cells and associated with autoimmune disease alter one or more of the 15 transcription factor motifs from the IRF9-centered network. This example and those in Figs. S11, S12, illustrate that disease-associated variants from the same or related disorders and traits repeatedly localize within the recognition sequences of transcription factors that form interacting regulatory networks.
