@article{aff284e465214b7f9040963cd67d77a4,
title = "Tissue-specific enhancer functional networks for associating distal regulatory regions to disease",
abstract = "Systematic study of tissue-specific function of enhancers and their disease associations is a major challenge. We present an integrative machine-learning framework, FENRIR, that integrates thousands of disparate epigenetic and functional genomics datasets to infer tissue-specific functional relationships between enhancers for 140 diverse human tissues and cell types, providing a regulatory-region-centric approach to systematically identify disease-associated enhancers. We demonstrated its power to accurately prioritize enhancers associated with 25 complex diseases. In a case study on autism, FENRIR-prioritized enhancers showed a significant proband-specific de novo mutation enrichment in a large, sibling-controlled cohort, indicating pathogenic signal. We experimentally validated transcriptional regulatory activities of eight enhancers, including enhancers not previously reported with autism, and demonstrated their differential regulatory potential between proband and sibling alleles. Thus, FENRIR is an accurate and effective framework for the study of tissue-specific enhancers and their role in disease. FENRIR can be accessed at fenrir.flatironinstitute.org/.",
keywords = "GWAS, autism, brain, de novo mutation, enhancer, functional network",
author = "Xi Chen and Jian Zhou and Ran Zhang and Wong, {Aaron K.} and Park, {Christopher Y.} and Theesfeld, {Chandra L.} and Troyanskaya, {Olga G.}",
note = "Funding Information: We are grateful to the families that participated in the SFARI SSC. This work is supported by NIH grants R01HG005998, U54HL117798, and R01GM071966; HHS grant HHSN272201000054C; and Simons Foundation grant 395506 to O.G.T. The authors acknowledge all members of the Troyanskaya laboratory at Princeton University for helpful discussions. We appreciate obtaining access to ASD genes on SFARI Base. We also thank the Simons Foundation and the Scientific Computing Core of the Flatiron Institute. X.C. J.Z. and O.G.T. conceived and designed the research. X.C. J.Z. and R.Z. performed method development and computational analyses with contributions from C.L.T. A.K.W. and C.Y.P. C.L.T. performed the experiments. A.K.W. developed the web interface. X.C. C.L.T. and O.G.T. wrote the manuscript with inputs from J.Z. C.Y.P. and A.K.W. The authors declare no competing interests. Funding Information: We are grateful to the families that participated in the SFARI SSC. This work is supported by NIH grants R01HG005998 , U54HL117798 , and R01GM071966 ; HHS grant HHSN272201000054C ; and Simons Foundation grant 395506 to O.G.T. The authors acknowledge all members of the Troyanskaya laboratory at Princeton University for helpful discussions. We appreciate obtaining access to ASD genes on SFARI Base. We also thank the Simons Foundation and the Scientific Computing Core of the Flatiron Institute. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = apr,
day = "21",
doi = "10.1016/j.cels.2021.02.002",
language = "English (US)",
volume = "12",
pages = "353--362.e6",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "4",
}