Large-scale transcriptome-wide association study identifies new prostate cancer risk regions

Research output: Contribution to journalJournal articleResearchpeer-review

  • Nicholas Mancuso
  • Simon Gayther
  • Alexander Gusev
  • Wei Zheng
  • Kathryn L. Penney
  • Zsofia Kote-Jarai
  • Rosalind Eeles
  • Matthew Freedman
  • Christopher Haiman
  • Bogdan Pasaniuc
  • Brian E. Henderson
  • Sara Benlloch
  • Fredrick R. Schumacher
  • Ali Amin Al Olama
  • Kenneth Muir
  • Sonja I. Berndt
  • David V. Conti
  • Fredrik Wiklund
  • Stephen Chanock
  • Victoria L. Stevens
  • Catherine M. Tangen
  • Jyotsna Batra
  • Judith Clements
  • Henrik Gronberg
  • Nora Pashayan
  • Johanna Schleutker
  • Demetrius Albanes
  • Stephanie Weinstein
  • Alicja Wolk
  • Catharine West
  • Lorelei Mucci
  • Géraldine Cancel-Tassin
  • Stella Koutros
  • Karina Dalsgaard Sorensen
  • Lovise Maehle
  • David E. Neal
  • Freddie C. Hamdy
  • Jenny L. Donovan
  • Ruth C. Travis
  • Robert J. Hamilton
  • Sue Ann Ingles
  • Barry Rosenstein
  • Yong Jie Lu
  • Graham G. Giles
  • Adam S. Kibel
  • Ana Vega
  • Manolis Kogevinas
  • Jong Y. Park
  • Janet L. Stanford
  • Nordestgaard, Børge
  • The Practical Consortium

Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here we integrate the largest PrCa GWAS (N = 142,392) with gene expression measured in 45 tissues (N = 4458), including normal and tumor prostate, to perform a multi-tissue transcriptome-wide association study (TWAS) for PrCa. We identify 217 genes at 84 independent 1 Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2 Mb. 23 genes are significant in TWAS only for alternative splicing models in prostate tumor thus supporting the hypothesis of splicing driving risk for continued oncogenesis. Finally, we use a Bayesian probabilistic approach to estimate credible sets of genes containing the causal gene at a pre-defined level; this reduced the list of 217 associations to 109 genes in the 90% credible set. Overall, our findings highlight the power of integrating expression with PrCa GWAS to identify novel risk loci and prioritize putative causal genes at known risk loci.

Original languageEnglish
Article number4079
JournalNature Communications
Volume9
Issue number1
Number of pages11
ISSN2041-1723
DOIs
Publication statusPublished - 2018

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