Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

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

Sylvan C. Baca, Cassandra Singler, Soumya Zacharia, Ji-Heui Seo, Tunc Morova, Faraz Hach, Yi Ding, Tommer Schwarz, Chia-Chi Flora Huang, 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, Matthew L. Freedman
doi: https://doi.org/10.1101/2021.05.10.443466
Sylvan C. Baca
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
3The Eli and Edythe L. Broad Institute, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cassandra Singler
4Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Soumya Zacharia
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ji-Heui Seo
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tunc Morova
5Vancouver Prostate Centre University of British Columbia, Vancouver, BC, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Faraz Hach
5Vancouver Prostate Centre University of British Columbia, Vancouver, BC, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yi Ding
6Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tommer Schwarz
6Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chia-Chi Flora Huang
5Vancouver Prostate Centre University of British Columbia, Vancouver, BC, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cynthia Kalita
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
7Division of Genetics, Brigham & Women’s Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefan Groha
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
3The Eli and Edythe L. Broad Institute, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark M. Pomerantz
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Victoria Wang
8Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA
9Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Simon Linder
10Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
11Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher J. Sweeney
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wilbert Zwart
10Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
11Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nathan A. Lack
5Vancouver Prostate Centre University of British Columbia, Vancouver, BC, Canada
12School of Medicine, Koç University, Istanbul, Turkey
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bogdan Pasaniuc
6Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA
13Department of Computational Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA USA
14Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
15Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David Y. Takeda
4Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alexander Gusev
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
3The Eli and Edythe L. Broad Institute, Cambridge, MA, USA
7Division of Genetics, Brigham & Women’s Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: freedman@broadinstitute.org
Matthew L. Freedman
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
3The Eli and Edythe L. Broad Institute, Cambridge, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: freedman@broadinstitute.org
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* These authors jointly supervised this work

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted May 11, 2021.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation
Sylvan C. Baca, Cassandra Singler, Soumya Zacharia, Ji-Heui Seo, Tunc Morova, Faraz Hach, Yi Ding, Tommer Schwarz, Chia-Chi Flora Huang, 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, Matthew L. Freedman
bioRxiv 2021.05.10.443466; doi: https://doi.org/10.1101/2021.05.10.443466
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation
Sylvan C. Baca, Cassandra Singler, Soumya Zacharia, Ji-Heui Seo, Tunc Morova, Faraz Hach, Yi Ding, Tommer Schwarz, Chia-Chi Flora Huang, 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, Matthew L. Freedman
bioRxiv 2021.05.10.443466; doi: https://doi.org/10.1101/2021.05.10.443466

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genetics
Subject Areas
All Articles
  • Animal Behavior and Cognition (3590)
  • Biochemistry (7562)
  • Bioengineering (5503)
  • Bioinformatics (20753)
  • Biophysics (10308)
  • Cancer Biology (7964)
  • Cell Biology (11625)
  • Clinical Trials (138)
  • Developmental Biology (6598)
  • Ecology (10177)
  • Epidemiology (2065)
  • Evolutionary Biology (13589)
  • Genetics (9530)
  • Genomics (12830)
  • Immunology (7917)
  • Microbiology (19525)
  • Molecular Biology (7651)
  • Neuroscience (42025)
  • Paleontology (307)
  • Pathology (1254)
  • Pharmacology and Toxicology (2195)
  • Physiology (3261)
  • Plant Biology (7028)
  • Scientific Communication and Education (1294)
  • Synthetic Biology (1949)
  • Systems Biology (5422)
  • Zoology (1113)