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

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; Børge G. Nordestgaard; The Practical Consortium

doi:10.1038/s41467-018-06302-1

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

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. StevensCatherine 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, Børge G. Nordestgaard, The Practical Consortium

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

38 Citationer (Scopus)

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Abstract

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.

Originalsprog	Engelsk
Artikelnummer	4079
Tidsskrift	Nature Communications
Vol/bind	9
Udgave nummer	1
Antal sider	11
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-018-06302-1
Status	Udgivet - 2018

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10.1038/s41467-018-06302-1Licens: CC BY

Large-scale transcriptome-wide association study identifies new prostate cancer risk regionsForlagets udgivne version, 915 KBLicens: CC BY

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Mancuso, N., Gayther, S., Gusev, A., Zheng, W., Penney, K. L., Kote-Jarai, Z., Eeles, R., Freedman, M., Haiman, C., Pasaniuc, B., Henderson, B. E., Benlloch, S., Schumacher, F. R., Olama, A. A. A., Muir, K., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S., ... The Practical Consortium (2018). Large-scale transcriptome-wide association study identifies new prostate cancer risk regions. Nature Communications, 9(1), [4079]. https://doi.org/10.1038/s41467-018-06302-1

Mancuso, N, Gayther, S, Gusev, A, Zheng, W, Penney, KL, Kote-Jarai, Z, Eeles, R, Freedman, M, Haiman, C, Pasaniuc, B, Henderson, BE, Benlloch, S, Schumacher, FR, Olama, AAA, Muir, K, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Pashayan, N, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Hamdy, FC, Donovan, JL, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, YJ, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Park, JY, Stanford, JL, Nordestgaard, BG & The Practical Consortium 2018, 'Large-scale transcriptome-wide association study identifies new prostate cancer risk regions', Nature Communications, bind 9, nr. 1, 4079. https://doi.org/10.1038/s41467-018-06302-1

@article{089ac45701d74dd4ab4a2162ae322871,

title = "Large-scale transcriptome-wide association study identifies new prostate cancer risk regions",

abstract = "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.",

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

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doi = "10.1038/s41467-018-06302-1",

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journal = "Nature Communications",

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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 - Nordestgaard, Børge G.

AU - The Practical Consortium

PY - 2018

Y1 - 2018

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.

U2 - 10.1038/s41467-018-06302-1

DO - 10.1038/s41467-018-06302-1

M3 - Journal article

C2 - 30287866

AN - SCOPUS:85054455296

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4079

ER -

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

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