Explaining the genetics of many diseases is challenging because most associations localize to incompletely characterized regulatory regions. We show that transcription factors (TFs) occupy multiple loci of individual complex genetic disorders using novel computational methods. Application to 213 phenotypes and 1,544 TF binding datasets identifies 2,264 relationships between hundreds of TFs and 94 phenotypes, including AR in prostate cancer and GATA3 in breast cancer. Strikingly, nearly half of the systemic lupus erythematosus risk loci are occupied by the Epstein-Barr virus EBNA2 protein and many co-clustering human TFs, revealing gene-environment interaction. Similar EBNA2-anchored associations exist in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis, and celiac disease. Instances of allele-dependent DNA binding and downstream effects on gene expression at plausibly causal variants support genetic mechanisms dependent upon EBNA2. Our results nominate mechanisms that operate across risk loci within disease phenotypes, suggesting new paradigms for disease origins.

The data presented support the view that follow-up liver biopsies, as recommended by published guidelines, for patients on long-term low-dose methotrexate can be avoided if PIIINP levels are consistently normal. This approach would have reduced the number of patients requiring biopsy in our series by 45%. The PIIINP assay will also be helpful in the management of patients on methotrexate in whom liver biopsy is contraindicated, and in patients with nonalcoholic steatohepatitis.