Abstract
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10 -6 , including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 968-978 |
| Number of pages | 11 |
| Journal | Nature Genetics |
| Volume | 50 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 2018 |
ASJC Scopus subject areas
- Genetics
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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer. / Wu, Lang; Shi, Wei; Long, Jirong; Guo, Xingyi; Michailidou, Kyriaki; Beesley, Jonathan; Bolla, Manjeet K.; Shu, Xiao Ou; Lu, Yingchang; Cai, Qiuyin; Al-Ejeh, Fares; Rozali, Esdy; Wang, Qin; Dennis, Joe; Li, Bingshan; Zeng, Chenjie; Feng, Helian; Gusev, Alexander; Barfield, Richard T.; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Aronson, Kristan J.; Auer, Paul L.; Barrdahl, Myrto; Baynes, Caroline; Beckmann, Matthias W.; Benitez, Javier; Bermisheva, Marina; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Brauch, Hiltrud; Brenner, Hermann; Brinton, Louise; Broberg, Per; Brucker, Sara Y.; Burwinkel, Barbara; Caldés, Trinidad; Canzian, Federico; Carter, Brian D.; Castelao, J. Esteban; Chang-Claude, Jenny; Chen, Xiaoqing; Cheng, Ting Yuan David; Christiansen, Hans; Clarke, Christine L.; Collée, Margriet; Cornelissen, Sten; Couch, Fergus J.; Cox, David; Cox, Angela; Cross, Simon S.; Cunningham, Julie M.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Doheny, Kimberly F.; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dumont, Martine; Dwek, Miriam; Eccles, Diana M.; Eilber, Ursula; Eliassen, A. Heather; Engel, Christoph; Eriksson, Mikael; Fachal, Laura; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fritschi, Lin; Gabrielson, Marike; Gago-Dominguez, Manuela; Gapstur, Susan M.; García-Closas, Montserrat; Gaudet, Mia M.; Ghoussaini, Maya; Giles, Graham G.; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Guénel, Pascal; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hall, Per; Hallberg, Emily; Hamann, Ute; Harrington, Patricia; Hein, Alexander; Hicks, Belynda; Hillemanns, Peter; Hollestelle, Antoinette; Hoover, Robert N.; Hopper, John L.; Huang, Guanmengqian; Humphreys, Keith; Hunter, David J.; Jakubowska, Anna; Janni, Wolfgang; John, Esther M.; Johnson, Nichola; Jones, Kristine; Jones, Michael E.; Jung, Audrey; Kaaks, Rudolf; Kerin, Michael J.; Khusnutdinova, Elza; Kosma, Veli Matti; Kristensen, Vessela N.; Lambrechts, Diether; Le Marchand, Loic; Li, Jingmei; Lindström, Sara; Lissowska, Jolanta; Lo, Wing Yee; Loibl, Sibylle; Lubinski, Jan; Luccarini, Craig; Lux, Michael P.; MacInnis, Robert J.; Maishman, Tom; Kostovska, Ivana Maleva; Mannermaa, Arto; Manson, Jo Ann E.; Margolin, Sara; Mavroudis, Dimitrios; Meijers-Heijboer, Hanne; Meindl, Alfons; Menon, Usha; Meyer, Jeffery; Mulligan, Anna Marie; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Nielsen, Sune F.; Nordestgaard, Børge G.; Olopade, Olufunmilayo I.; Olson, Janet E.; Olsson, Håkan; Peterlongo, Paolo; Peto, Julian; Plaseska-Karanfilska, Dijana; Prentice, Ross; Presneau, Nadege; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rennert, Gad; Rennert, Hedy S.; Rhenius, Valerie; Romero, Atocha; Romm, Jane; Rudolph, Anja; Saloustros, Emmanouil; Sandler, Dale P.; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Schneeweiss, Andreas; Scott, Rodney J.; Scott, Christopher G.; Seal, Sheila; Shah, Mitul; Shrubsole, Martha J.; Smeets, Ann; Southey, Melissa C.; Spinelli, John J.; Stone, Jennifer; Surowy, Harald; Swerdlow, Anthony J.; Tamimi, Rulla M.; Tapper, William; Taylor, Jack A.; Terry, Mary Beth; Tessier, Daniel C.; Thomas, Abigail; Thöne, Kathrin; Tollenaar, Rob A.E.M.; Torres, Diana; Truong, Thérèse; Untch, Michael; Vachon, Celine; Van Den Berg, David; Vincent, Daniel; Waisfisz, Quinten; Weinberg, Clarice R.; Wendt, Camilla; Whittemore, Alice S.; Wildiers, Hans; Willett, Walter C.; Winqvist, Robert; Wolk, Alicja; Xia, Lucy; Yang, Xiaohong R.; Ziogas, Argyrios; Ziv, Elad; Dunning, Alison M.; Pharoah, Paul D.P.; Simard, Jacques; Milne, Roger L.; Edwards, Stacey L.; Kraft, Peter; Easton, Douglas F.; Chenevix-Trench, Georgia; Zheng, Wei.
In: Nature Genetics, Vol. 50, No. 7, 01.07.2018, p. 968-978.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer
AU - Wu, Lang
AU - Shi, Wei
AU - Long, Jirong
AU - Guo, Xingyi
AU - Michailidou, Kyriaki
AU - Beesley, Jonathan
AU - Bolla, Manjeet K.
AU - Shu, Xiao Ou
AU - Lu, Yingchang
AU - Cai, Qiuyin
AU - Al-Ejeh, Fares
AU - Rozali, Esdy
AU - Wang, Qin
AU - Dennis, Joe
AU - Li, Bingshan
AU - Zeng, Chenjie
AU - Feng, Helian
AU - Gusev, Alexander
AU - Barfield, Richard T.
AU - Andrulis, Irene L.
AU - Anton-Culver, Hoda
AU - Arndt, Volker
AU - Aronson, Kristan J.
AU - Auer, Paul L.
AU - Barrdahl, Myrto
AU - Baynes, Caroline
AU - Beckmann, Matthias W.
AU - Benitez, Javier
AU - Bermisheva, Marina
AU - Blomqvist, Carl
AU - Bogdanova, Natalia V.
AU - Bojesen, Stig E.
AU - Brauch, Hiltrud
AU - Brenner, Hermann
AU - Brinton, Louise
AU - Broberg, Per
AU - Brucker, Sara Y.
AU - Burwinkel, Barbara
AU - Caldés, Trinidad
AU - Canzian, Federico
AU - Carter, Brian D.
AU - Castelao, J. Esteban
AU - Chang-Claude, Jenny
AU - Chen, Xiaoqing
AU - Cheng, Ting Yuan David
AU - Christiansen, Hans
AU - Clarke, Christine L.
AU - Collée, Margriet
AU - Cornelissen, Sten
AU - Couch, Fergus J.
AU - Cox, David
AU - Cox, Angela
AU - Cross, Simon S.
AU - Cunningham, Julie M.
AU - Czene, Kamila
AU - Daly, Mary B.
AU - Devilee, Peter
AU - Doheny, Kimberly F.
AU - Dörk, Thilo
AU - Dos-Santos-Silva, Isabel
AU - Dumont, Martine
AU - Dwek, Miriam
AU - Eccles, Diana M.
AU - Eilber, Ursula
AU - Eliassen, A. Heather
AU - Engel, Christoph
AU - Eriksson, Mikael
AU - Fachal, Laura
AU - Fasching, Peter A.
AU - Figueroa, Jonine
AU - Flesch-Janys, Dieter
AU - Fletcher, Olivia
AU - Flyger, Henrik
AU - Fritschi, Lin
AU - Gabrielson, Marike
AU - Gago-Dominguez, Manuela
AU - Gapstur, Susan M.
AU - García-Closas, Montserrat
AU - Gaudet, Mia M.
AU - Ghoussaini, Maya
AU - Giles, Graham G.
AU - Goldberg, Mark S.
AU - Goldgar, David E.
AU - González-Neira, Anna
AU - Guénel, Pascal
AU - Hahnen, Eric
AU - Haiman, Christopher A.
AU - Håkansson, Niclas
AU - Hall, Per
AU - Hallberg, Emily
AU - Hamann, Ute
AU - Harrington, Patricia
AU - Hein, Alexander
AU - Hicks, Belynda
AU - Hillemanns, Peter
AU - Hollestelle, Antoinette
AU - Hoover, Robert N.
AU - Hopper, John L.
AU - Huang, Guanmengqian
AU - Humphreys, Keith
AU - Hunter, David J.
AU - Jakubowska, Anna
AU - Janni, Wolfgang
AU - John, Esther M.
AU - Johnson, Nichola
AU - Jones, Kristine
AU - Jones, Michael E.
AU - Jung, Audrey
AU - Kaaks, Rudolf
AU - Kerin, Michael J.
AU - Khusnutdinova, Elza
AU - Kosma, Veli Matti
AU - Kristensen, Vessela N.
AU - Lambrechts, Diether
AU - Le Marchand, Loic
AU - Li, Jingmei
AU - Lindström, Sara
AU - Lissowska, Jolanta
AU - Lo, Wing Yee
AU - Loibl, Sibylle
AU - Lubinski, Jan
AU - Luccarini, Craig
AU - Lux, Michael P.
AU - MacInnis, Robert J.
AU - Maishman, Tom
AU - Kostovska, Ivana Maleva
AU - Mannermaa, Arto
AU - Manson, Jo Ann E.
AU - Margolin, Sara
AU - Mavroudis, Dimitrios
AU - Meijers-Heijboer, Hanne
AU - Meindl, Alfons
AU - Menon, Usha
AU - Meyer, Jeffery
AU - Mulligan, Anna Marie
AU - Neuhausen, Susan L.
AU - Nevanlinna, Heli
AU - Neven, Patrick
AU - Nielsen, Sune F.
AU - Nordestgaard, Børge G.
AU - Olopade, Olufunmilayo I.
AU - Olson, Janet E.
AU - Olsson, Håkan
AU - Peterlongo, Paolo
AU - Peto, Julian
AU - Plaseska-Karanfilska, Dijana
AU - Prentice, Ross
AU - Presneau, Nadege
AU - Pylkäs, Katri
AU - Rack, Brigitte
AU - Radice, Paolo
AU - Rahman, Nazneen
AU - Rennert, Gad
AU - Rennert, Hedy S.
AU - Rhenius, Valerie
AU - Romero, Atocha
AU - Romm, Jane
AU - Rudolph, Anja
AU - Saloustros, Emmanouil
AU - Sandler, Dale P.
AU - Sawyer, Elinor J.
AU - Schmidt, Marjanka K.
AU - Schmutzler, Rita K.
AU - Schneeweiss, Andreas
AU - Scott, Rodney J.
AU - Scott, Christopher G.
AU - Seal, Sheila
AU - Shah, Mitul
AU - Shrubsole, Martha J.
AU - Smeets, Ann
AU - Southey, Melissa C.
AU - Spinelli, John J.
AU - Stone, Jennifer
AU - Surowy, Harald
AU - Swerdlow, Anthony J.
AU - Tamimi, Rulla M.
AU - Tapper, William
AU - Taylor, Jack A.
AU - Terry, Mary Beth
AU - Tessier, Daniel C.
AU - Thomas, Abigail
AU - Thöne, Kathrin
AU - Tollenaar, Rob A.E.M.
AU - Torres, Diana
AU - Truong, Thérèse
AU - Untch, Michael
AU - Vachon, Celine
AU - Van Den Berg, David
AU - Vincent, Daniel
AU - Waisfisz, Quinten
AU - Weinberg, Clarice R.
AU - Wendt, Camilla
AU - Whittemore, Alice S.
AU - Wildiers, Hans
AU - Willett, Walter C.
AU - Winqvist, Robert
AU - Wolk, Alicja
AU - Xia, Lucy
AU - Yang, Xiaohong R.
AU - Ziogas, Argyrios
AU - Ziv, Elad
AU - Dunning, Alison M.
AU - Pharoah, Paul D.P.
AU - Simard, Jacques
AU - Milne, Roger L.
AU - Edwards, Stacey L.
AU - Kraft, Peter
AU - Easton, Douglas F.
AU - Chenevix-Trench, Georgia
AU - Zheng, Wei
N1 - Funding Information: The authors thank J. He, W. Wen, A. Giri and T. Edwards of Vanderbilt Epidemiology Center and R. Tao of the Department of Biostatistics, Vanderbilt University Medical Center for their help with the data analysis of this study. The authors would also like to thank all of the individuals for their participation in the parent studies and all of the researchers, clinicians, technicians and administrative staff for their contribution to the studies. We are also grateful to H. K. Im of University of Chicago for her help. The data analyses were conducted using the Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University. This project at Vanderbilt University Medical Center was supported in part by grants R01CA158473 and R01CA148677 from the US National Institutes of Health as well as funds from Anne Potter Wilson endowment. L.W. is supported by NCI K99 CA218892 and the Vanderbilt Molecular and Genetic Epidemiology of Cancer (MAGEC) training program (US NCI grant R25 CA160056 awarded to X.-O.S.). Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Genome Québec and the Quebec Breast Cancer Foundation; the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (National Institutes of Health (NIH) grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/ A10118 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec—grant no. PSR-SIIRI-701. Combining of the GWAS data was supported in part by the NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE, part of the GAME-ON initiative). A full description of funding and acknowledgments for BCAC studies, along with consortium membership, are included in the Supplementary Note. Publisher Copyright: © 2018 The Author(s).
PY - 2018/7/1
Y1 - 2018/7/1
N2 - The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10 -6 , including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
AB - The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10 -6 , including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
UR - http://www.scopus.com/inward/record.url?scp=85048695897&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048695897&partnerID=8YFLogxK
U2 - 10.1038/s41588-018-0132-x
DO - 10.1038/s41588-018-0132-x
M3 - Article
C2 - 29915430
AN - SCOPUS:85048695897
VL - 50
SP - 968
EP - 978
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 7
ER -