Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

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dc.contributor.authorBaca, S.C.
dc.contributor.authorSingler, C.
dc.contributor.authorZacharia, S.
dc.contributor.authorSeo, J.H.
dc.contributor.authorMorova, T.
dc.contributor.authorHach, F.
dc.contributor.authorDing, Y.
dc.contributor.authorSchwarz, T.
dc.contributor.authorHuang, C.C.F.
dc.contributor.authorAnderson, J.
dc.contributor.authorFay, A.P.
dc.contributor.authorKalita, C.
dc.contributor.authorGroha, S.
dc.contributor.authorPomerantz, M.M.
dc.contributor.authorWang, V.
dc.contributor.authorLinder, S.
dc.contributor.authorSweeney, C.J.
dc.contributor.authorZwart, W.
dc.contributor.authorLack, N.A.
dc.contributor.authorPasaniuc, B.
dc.contributor.authoret al.
dc.date.issued2022
dc.description.abstractMany genetic variants affect disease risk by altering context-dependent gene regulation. Such variants are difficult to study mechanistically using current methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs). To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for identifying genotypic and allele-specific effects on chromatin that are also associated with disease. In prostate cancer, CWAS identified regulatory elements and androgen receptor-binding sites that explained the association at 52 of 98 known prostate cancer risk loci and discovered 17 additional risk loci. CWAS implicated key developmental transcription factors in prostate cancer risk that are overlooked by eQTL-based approaches due to context-dependent gene regulation. We experimentally validated associations and demonstrated the extensibility of CWAS to additional epigenomic datasets and phenotypes, including response to prostate cancer treatment. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting transcriptional regulation.
dc.description.statementofresponsibilitySylvan C. Baca, Cassandra Singler, Soumya Zacharia, Ji-Heui Seo, Tunc Morova, Faraz Hach, Yi Ding, Tommer Schwarz, Chia-Chi Flora Huang, Jacob Anderson, André P. Fay, Cynthia Kalita, Stefan Groha, Mark M. Pomerantz, Victoria Wang, Simon Linder, Christopher J. Sweeney, Wilbert Zwart, Nathan A. Lack, Bogdan Pasaniuc, David Y. Takeda, Alexander Gusev, and Matthew L. Freedman
dc.identifier.citationNature Genetics, 2022; 54(9):1364-1375
dc.identifier.doi10.1038/s41588-022-01168-y
dc.identifier.issn1061-4036
dc.identifier.issn1546-1718
dc.identifier.orcidSweeney, C.J. [0000-0002-0398-6018]
dc.identifier.urihttps://hdl.handle.net/2440/146062
dc.language.isoen
dc.publisherNature Research
dc.rights© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
dc.source.urihttps://doi.org/10.1038/s41588-022-01168-y
dc.subjectEpigenomics; Genome informatics; Prostate cancer
dc.subject.meshChromatin
dc.subject.meshHumans
dc.subject.meshProstatic Neoplasms
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshGene Expression Regulation
dc.subject.meshPolymorphism, Single Nucleotide
dc.subject.meshQuantitative Trait Loci
dc.subject.meshMale
dc.subject.meshGenome-Wide Association Study
dc.titleGenetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation
dc.typeJournal article
pubs.publication-statusPublished

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