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Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity
- Source :
- Nature genetics
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
Abstract
- Explaining the genetics of many diseases is challenging because most associations localize to incompletely characterized regulatory regions. Using new computational methods, we show that transcription factors (TFs) occupy multiple loci associated with individual complex genetic disorders. Application to 213 phenotypes and 1,544 TF binding datasets identified 2,264 relationships between hundreds of TFs and 94 phenotypes, including androgen receptor in prostate cancer and GATA3 in breast cancer. Strikingly, nearly half of systemic lupus erythematosus risk loci are occupied by the Epstein–Barr virus EBNA2 protein and many coclustering human TFs, showing 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 on EBNA2. Our results nominate mechanisms that operate across risk loci within disease phenotypes, suggesting new models for disease origins.
- Subjects :
- 0301 basic medicine
Regulation of gene expression
Genetics
Epstein-Barr Virus Infections
Herpesvirus 4, Human
Lupus erythematosus
Autoimmunity
Disease
Biology
medicine.disease_cause
medicine.disease
Article
Human genetics
3. Good health
Androgen receptor
03 medical and health sciences
030104 developmental biology
medicine
Humans
Gene-Environment Interaction
Functional genomics
Transcription factor
Transcription Factors
Subjects
Details
- ISSN :
- 15461718 and 10614036
- Volume :
- 50
- Database :
- OpenAIRE
- Journal :
- Nature Genetics
- Accession number :
- edsair.doi.dedup.....f01ed4a12848c731963affd5890aaf5a
- Full Text :
- https://doi.org/10.1038/s41588-018-0102-3