Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Ali Amin Al Olama; Tokhir Dadaev; Dennis J Hazelett; Qiuyan Li; Daniel Leongamornlert; Edward J Saunders; Sarah Stephens; Clara Cieza-Borrella; Ian Whitmore; Sara Benlloch Garcia; Graham G Giles; Melissa C Southey; Liesel Fitzgerald; Henrik Gronberg; Fredrik Wiklund; Markus Aly; Brian E Henderson; Fredrick Schumacher; Christopher A Haiman; Johanna Schleutker; Tiina Wahlfors; Teuvo L Tammela; Børge G Nordestgaard; Tim J Key; Ruth C Travis; David E Neal; Jenny L Donovan; Freddie C Hamdy; Paul Pharoah; Nora Pashayan; Kay-Tee Khaw; Janet L Stanford; Stephen N Thibodeau; Shannon K Mcdonnell; Daniel J Schaid; Christiane Maier; Walther Vogel; Manuel Luedeke; Kathleen Herkommer; Adam S Kibel; Cezary Cybulski; Dominika Wokołorczyk; Wojciech Kluzniak; Lisa Cannon-Albright; Hermann Brenner; Katja Butterbach; Volker Arndt; Jong Y Park; Thomas Sellers; Hui-Yi Lin; PRACTICAL Consortium

doi:10.1093/hmg/ddv203

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Ali Amin Al Olama, Tokhir Dadaev, Dennis J Hazelett, Qiuyan Li, Daniel Leongamornlert, Edward J Saunders, Sarah Stephens, Clara Cieza-Borrella, Ian Whitmore, Sara Benlloch Garcia, Graham G Giles, Melissa C Southey, Liesel Fitzgerald, Henrik Gronberg, Fredrik Wiklund, Markus Aly, Brian E Henderson, Fredrick Schumacher, Christopher A Haiman, Johanna SchleutkerTiina Wahlfors, Teuvo L Tammela, Børge G Nordestgaard, Tim J Key, Ruth C Travis, David E Neal, Jenny L Donovan, Freddie C Hamdy, Paul Pharoah, Nora Pashayan, Kay-Tee Khaw, Janet L Stanford, Stephen N Thibodeau, Shannon K Mcdonnell, Daniel J Schaid, Christiane Maier, Walther Vogel, Manuel Luedeke, Kathleen Herkommer, Adam S Kibel, Cezary Cybulski, Dominika Wokołorczyk, Wojciech Kluzniak, Lisa Cannon-Albright, Hermann Brenner, Katja Butterbach, Volker Arndt, Jong Y Park, Thomas Sellers, Hui-Yi Lin, PRACTICAL Consortium

Department of Clinical Medicine

48 Citations (Scopus)

Abstract

Genome-wide association studies (GWAS) have identified numerouscommon prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variationwas observed at 39 regions; 35 of which are nowdescribed by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-AsianGWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci nowexplain ~38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reportedGWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

Original language	English
Journal	Human Molecular Genetics
Volume	24
Issue number	19
Pages (from-to)	5589-602
Number of pages	14
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddv203
Publication status	Published - 1 Oct 2015

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Amin Al Olama, A., Dadaev, T., Hazelett, D. J., Li, Q., Leongamornlert, D., Saunders, E. J., Stephens, S., Cieza-Borrella, C., Whitmore, I., Benlloch Garcia, S., Giles, G. G., Southey, M. C., Fitzgerald, L., Gronberg, H., Wiklund, F., Aly, M., Henderson, B. E., Schumacher, F., Haiman, C. A., ... PRACTICAL Consortium (2015). Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans. Human Molecular Genetics, 24(19), 5589-602. https://doi.org/10.1093/hmg/ddv203

Amin Al Olama, A, Dadaev, T, Hazelett, DJ, Li, Q, Leongamornlert, D, Saunders, EJ, Stephens, S, Cieza-Borrella, C, Whitmore, I, Benlloch Garcia, S, Giles, GG, Southey, MC, Fitzgerald, L, Gronberg, H, Wiklund, F, Aly, M, Henderson, BE, Schumacher, F, Haiman, CA, Schleutker, J, Wahlfors, T, Tammela, TL, Nordestgaard, BG, Key, TJ, Travis, RC, Neal, DE, Donovan, JL, Hamdy, FC, Pharoah, P, Pashayan, N, Khaw, K-T, Stanford, JL, Thibodeau, SN, Mcdonnell, SK, Schaid, DJ, Maier, C, Vogel, W, Luedeke, M, Herkommer, K, Kibel, AS, Cybulski, C, Wokołorczyk, D, Kluzniak, W, Cannon-Albright, L, Brenner, H, Butterbach, K, Arndt, V, Park, JY, Sellers, T, Lin, H-Y & PRACTICAL Consortium 2015, 'Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans', Human Molecular Genetics, vol. 24, no. 19, pp. 5589-602. https://doi.org/10.1093/hmg/ddv203

@article{193b52da4fe0463da16bfa6065cff066,

title = "Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans",

abstract = "Genome-wide association studies (GWAS) have identified numerouscommon prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variationwas observed at 39 regions; 35 of which are nowdescribed by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-AsianGWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci nowexplain ~38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reportedGWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.",

author = "{Amin Al Olama}, Ali and Tokhir Dadaev and Hazelett, {Dennis J} and Qiuyan Li and Daniel Leongamornlert and Saunders, {Edward J} and Sarah Stephens and Clara Cieza-Borrella and Ian Whitmore and {Benlloch Garcia}, Sara and Giles, {Graham G} and Southey, {Melissa C} and Liesel Fitzgerald and Henrik Gronberg and Fredrik Wiklund and Markus Aly and Henderson, {Brian E} and Fredrick Schumacher and Haiman, {Christopher A} and Johanna Schleutker and Tiina Wahlfors and Tammela, {Teuvo L} and Nordestgaard, {B{\o}rge G} and Key, {Tim J} and Travis, {Ruth C} and Neal, {David E} and Donovan, {Jenny L} and Hamdy, {Freddie C} and Paul Pharoah and Nora Pashayan and Kay-Tee Khaw and Stanford, {Janet L} and Thibodeau, {Stephen N} and Mcdonnell, {Shannon K} and Schaid, {Daniel J} and Christiane Maier and Walther Vogel and Manuel Luedeke and Kathleen Herkommer and Kibel, {Adam S} and Cezary Cybulski and Dominika Woko{\l}orczyk and Wojciech Kluzniak and Lisa Cannon-Albright and Hermann Brenner and Katja Butterbach and Volker Arndt and Park, {Jong Y} and Thomas Sellers and Hui-Yi Lin and {PRACTICAL Consortium}",

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T1 - Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

AU - Amin Al Olama, Ali

AU - Dadaev, Tokhir

AU - Hazelett, Dennis J

AU - Li, Qiuyan

AU - Leongamornlert, Daniel

AU - Saunders, Edward J

AU - Stephens, Sarah

AU - Cieza-Borrella, Clara

AU - Whitmore, Ian

AU - Benlloch Garcia, Sara

AU - Giles, Graham G

AU - Southey, Melissa C

AU - Fitzgerald, Liesel

AU - Gronberg, Henrik

AU - Wiklund, Fredrik

AU - Aly, Markus

AU - Henderson, Brian E

AU - Schumacher, Fredrick

AU - Haiman, Christopher A

AU - Schleutker, Johanna

AU - Wahlfors, Tiina

AU - Tammela, Teuvo L

AU - Nordestgaard, Børge G

AU - Key, Tim J

AU - Travis, Ruth C

AU - Neal, David E

AU - Donovan, Jenny L

AU - Hamdy, Freddie C

AU - Pharoah, Paul

AU - Pashayan, Nora

AU - Khaw, Kay-Tee

AU - Stanford, Janet L

AU - Thibodeau, Stephen N

AU - Mcdonnell, Shannon K

AU - Schaid, Daniel J

AU - Maier, Christiane

AU - Vogel, Walther

AU - Luedeke, Manuel

AU - Herkommer, Kathleen

AU - Kibel, Adam S

AU - Cybulski, Cezary

AU - Wokołorczyk, Dominika

AU - Kluzniak, Wojciech

AU - Cannon-Albright, Lisa

AU - Brenner, Hermann

AU - Butterbach, Katja

AU - Arndt, Volker

AU - Park, Jong Y

AU - Sellers, Thomas

AU - Lin, Hui-Yi

AU - PRACTICAL Consortium

PY - 2015/10/1

Y1 - 2015/10/1

N2 - Genome-wide association studies (GWAS) have identified numerouscommon prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variationwas observed at 39 regions; 35 of which are nowdescribed by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-AsianGWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci nowexplain ~38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reportedGWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

AB - Genome-wide association studies (GWAS) have identified numerouscommon prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variationwas observed at 39 regions; 35 of which are nowdescribed by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-AsianGWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci nowexplain ~38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reportedGWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

U2 - 10.1093/hmg/ddv203

DO - 10.1093/hmg/ddv203

M3 - Journal article

C2 - 26025378

SN - 0964-6906

VL - 24

SP - 5589

EP - 5602

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 19

ER -

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

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