TY - JOUR
T1 - Large-scale transcriptome-wide association study identifies new prostate cancer risk regions
AU - Mancuso, Nicholas
AU - Gayther, Simon
AU - Gusev, Alexander
AU - Zheng, Wei
AU - Penney, Kathryn L.
AU - Kote-Jarai, Zsofia
AU - Eeles, Rosalind
AU - Freedman, Matthew
AU - Haiman, Christopher
AU - Pasaniuc, Bogdan
AU - Henderson, Brian E.
AU - Benlloch, Sara
AU - Schumacher, Fredrick R.
AU - Olama, Ali Amin Al
AU - Muir, Kenneth
AU - Berndt, Sonja I.
AU - Conti, David V.
AU - Wiklund, Fredrik
AU - Chanock, Stephen
AU - Stevens, Victoria L.
AU - Tangen, Catherine M.
AU - Batra, Jyotsna
AU - Clements, Judith
AU - Gronberg, Henrik
AU - Pashayan, Nora
AU - Schleutker, Johanna
AU - Albanes, Demetrius
AU - Weinstein, Stephanie
AU - Wolk, Alicja
AU - West, Catharine
AU - Mucci, Lorelei
AU - Cancel-Tassin, Géraldine
AU - Koutros, Stella
AU - Sorensen, Karina Dalsgaard
AU - Maehle, Lovise
AU - Neal, David E.
AU - Hamdy, Freddie C.
AU - Donovan, Jenny L.
AU - Travis, Ruth C.
AU - Hamilton, Robert J.
AU - Ingles, Sue Ann
AU - Rosenstein, Barry
AU - Lu, Yong Jie
AU - Giles, Graham G.
AU - Kibel, Adam S.
AU - Vega, Ana
AU - Kogevinas, Manolis
AU - Park, Jong Y.
AU - Stanford, Janet L.
AU - Cybulski, Cezary
AU - Nordestgaard, Børge G.
AU - Brenner, Hermann
AU - Maier, Christiane
AU - Kim, Jeri
AU - John, Esther M.
AU - Teixeira, Manuel R.
AU - Neuhausen, Susan L.
AU - De Ruyck, Kim
AU - Razack, Azad
AU - Newcomb, Lisa F.
AU - Lessel, Davor
AU - Kaneva, Radka
AU - Usmani, Nawaid
AU - Claessens, Frank
AU - Townsend, Paul A.
AU - Dominguez, Manuela Gago
AU - Roobol, Monique J.
AU - Menegaux, Florence
AU - Khaw, Kay Tee
AU - Cannon-Albright, Lisa
AU - Pandha, Hardev
AU - Thibodeau, Stephen N.
AU - Hunter, David J.
AU - Kraft, Peter
AU - The PRACTICAL consortium
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
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 = 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.
UR - http://www.scopus.com/inward/record.url?scp=85054455296&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-06302-1
DO - 10.1038/s41467-018-06302-1
M3 - Article
C2 - 30287866
AN - SCOPUS:85054455296
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4079
ER -