Back to Search Start Over

Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity

Authors :
Carmy Forney
Matthew T. Weirauch
Masashi Yukawa
Daniel Miller
Xiaoting Chen
John B. Harley
Kashish Chetal
Albert F. Magnusen
Artem Barski
Leah C. Kottyan
Nathan Salomonis
Mario Pujato
Kenneth M. Kaufman
Arthur Lynch
Avery Maddox
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.

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