RT Journal Article
SR Electronic
T1 Large-scale transcriptome-wide association study identifies new prostate cancer risk regions
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 345736
DO 10.1101/345736
A1 Mancuso, Nicholas
A1 Gayther, Simon
A1 Gusev, Alexander
A1 Zheng, Wei
A1 Penney, Kathryn L.
A1 consortium the PRACTICAL, CRUK, BPC3, CAPS, PEGASUS
A1 Kote-Jarai, Zsofia
A1 Eeles, Rosalind
A1 Freedman, Matthew
A1 Haiman, Christopher
A1 Pasaniuc, Bogdan
YR 2018
UL http://biorxiv.org/content/early/2018/06/14/345736.abstract
AB 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=4,458), including normal and tumor prostate, to perform a multi-tissue transcriptomewide association study (TWAS) for PrCa. We identify 235 genes at 87 independent 1Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2Mb. 24 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 pre-defined level; this reduced the list of 235 associations to 120 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.