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

Multi-Tissue Transcriptome-Wide Association Study Identifies 26 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer

Alexander Gusev, Kate Lawrenson, Felipe Segato, Marcos A.S. Fonseca, Siddhartha Kar, Kevin C. Vavra, Janet M Lee, Tanya Pejovic, Ovarian Cancer Association Consortium, Beth Y. Karlan, Matthew L. Freedman, Houtan Noushmehr, Paul D.P. Pharoah, Bogdan Pasaniuc, Simon A. Gayther
doi: https://doi.org/10.1101/330613
Alexander Gusev
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
  • For correspondence: simon.gayther@cshs.org alexander_gusev@dfci.harvard.edu BPasaniuc@mednet.ucla.edu
Kate Lawrenson
2Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA, USA
3Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Felipe Segato
4Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, 14049-900, Brazil
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marcos A.S. Fonseca
4Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, 14049-900, Brazil
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Siddhartha Kar
5CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevin C. Vavra
2Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Janet M Lee
3Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tanya Pejovic
6Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA
7Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Beth Y. Karlan
2Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew L. Freedman
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
Houtan Noushmehr
4Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, 14049-900, Brazil
8Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul D.P. Pharoah
5CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bogdan Pasaniuc
9Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
10Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
11Department of Biomathematics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: simon.gayther@cshs.org alexander_gusev@dfci.harvard.edu BPasaniuc@mednet.ucla.edu
Simon A. Gayther
3Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: simon.gayther@cshs.org alexander_gusev@dfci.harvard.edu BPasaniuc@mednet.ucla.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

ABSTRACT

Genome-wide association studies (GWASs) have identified about 30 different susceptibility loci associated with high grade serous ovarian cancer (HGSOC) risk. We sought to identify potential susceptibility genes by integrating the risk variants at these regions with genetic variants impacting gene expression and splicing of nearby genes. We compiled gene expression and genotyping data from 2,169 samples for 6 different HGSOC-relevant tissue types. We integrated these data with GWAS data from 13,037 HGSOC cases and 40,941 controls, and performed a transcriptome-wide association study (TWAS) across >70,000 significantly heritable gene/exon features. We identified 24 transcriptome-wide significant associations for 14 unique genes, plus 90 significant exon-level associations in 20 unique genes. We implicated multiple novel genes at risk loci, e.g. LRRC46 at 19q21.32 (TWAS P=1×10−9) and a PRC1 splicing event (TWAS P=9×10−8) which was splice-variant specific and exhibited no eQTL signal. Functional analyses in HGSOC cell lines found evidence of essentiality for GOSR2, INTS1, KANSL1 and PRC1; with the latter gene showing levels of essentiality comparable to that of MYC. Overall, gene expression and splicing events explained 41% of SNP-heritability for HGSOC (s.e. 11%, P=2.5×10−4), implicated at least one target gene for 6/13 distinct genome-wide significant regions and revealed 2 known and 26 novel candidate susceptibility genes for HGSOC.

STATEMENT OF SIGNIFICANCE For many ovarian cancer risk regions, the target genes regulated by germline genetic variants are unknown. Using expression data from >2,100 individuals, this study identified novel associations of genes and splicing variants with ovarian cancer risk; with transcriptional variation now explaining over one-third of the SNP-heritability for this disease.

Footnotes

  • † jointly directed the study

  • Conflict of Interest: The authors have no financial conflicts of interest to declare.

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 25, 2018.
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.
Multi-Tissue Transcriptome-Wide Association Study Identifies 26 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer
(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
Multi-Tissue Transcriptome-Wide Association Study Identifies 26 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer
Alexander Gusev, Kate Lawrenson, Felipe Segato, Marcos A.S. Fonseca, Siddhartha Kar, Kevin C. Vavra, Janet M Lee, Tanya Pejovic, Ovarian Cancer Association Consortium, Beth Y. Karlan, Matthew L. Freedman, Houtan Noushmehr, Paul D.P. Pharoah, Bogdan Pasaniuc, Simon A. Gayther
bioRxiv 330613; doi: https://doi.org/10.1101/330613
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Multi-Tissue Transcriptome-Wide Association Study Identifies 26 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer
Alexander Gusev, Kate Lawrenson, Felipe Segato, Marcos A.S. Fonseca, Siddhartha Kar, Kevin C. Vavra, Janet M Lee, Tanya Pejovic, Ovarian Cancer Association Consortium, Beth Y. Karlan, Matthew L. Freedman, Houtan Noushmehr, Paul D.P. Pharoah, Bogdan Pasaniuc, Simon A. Gayther
bioRxiv 330613; doi: https://doi.org/10.1101/330613

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

  • Genomics
Subject Areas
All Articles
  • Animal Behavior and Cognition (4119)
  • Biochemistry (8828)
  • Bioengineering (6532)
  • Bioinformatics (23486)
  • Biophysics (11806)
  • Cancer Biology (9223)
  • Cell Biology (13336)
  • Clinical Trials (138)
  • Developmental Biology (7444)
  • Ecology (11425)
  • Epidemiology (2066)
  • Evolutionary Biology (15174)
  • Genetics (10453)
  • Genomics (14056)
  • Immunology (9188)
  • Microbiology (22200)
  • Molecular Biology (8823)
  • Neuroscience (47627)
  • Paleontology (351)
  • Pathology (1431)
  • Pharmacology and Toxicology (2493)
  • Physiology (3736)
  • Plant Biology (8090)
  • Scientific Communication and Education (1438)
  • Synthetic Biology (2225)
  • Systems Biology (6042)
  • Zoology (1254)