A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Lang Wu; Wei Shi; Jirong Long; Xingyi Guo; Kyriaki Michailidou; Jonathan Beesley; Manjeet K. Bolla; Xiao Ou Shu; Yingchang Lu; Qiuyin Cai; Fares Al-Ejeh; Esdy Rozali; Qin Wang; Joe Dennis; Bingshan Li; Chenjie Zeng; Helian Feng; Alexander Gusev; Richard T. Barfield; Irene L. Andrulis; Hoda Anton-Culver; Volker Arndt; Kristan J. Aronson; Paul L. Auer; Myrto Barrdahl; Caroline Baynes; Matthias W. Beckmann; Javier Benitez; Marina Bermisheva; Carl Blomqvist; Natalia V. Bogdanova; Stig E. Bojesen; Hiltrud Brauch; Hermann Brenner; Louise Brinton; Per Broberg; Sara Y. Brucker; Barbara Burwinkel; Trinidad Caldés; Federico Canzian; Brian D. Carter; J. Esteban Castelao; Jenny Chang-Claude; Xiaoqing Chen; Ting Yuan David Cheng; Hans Christiansen; Christine L. Clarke; Margriet Collée; Sten Cornelissen; Fergus J. Couch; David Cox; Angela Cox; Simon S. Cross; Julie M. Cunningham; Kamila Czene; Mary B. Daly; Peter Devilee; Kimberly F. Doheny; Thilo Dörk; Isabel Dos-Santos-Silva; Martine Dumont; Miriam Dwek; Diana M. Eccles; Ursula Eilber; A. Heather Eliassen; Christoph Engel; Mikael Eriksson; Laura Fachal; Peter A. Fasching; Jonine Figueroa; Dieter Flesch-Janys; Olivia Fletcher; Henrik Flyger; Lin Fritschi; Marike Gabrielson; Manuela Gago-Dominguez; Susan M. Gapstur; Montserrat García-Closas; Mia M. Gaudet; Maya Ghoussaini; Graham G. Giles; Mark S. Goldberg; David E. Goldgar; Anna González-Neira; Pascal Guénel; Eric Hahnen; Christopher A. Haiman; Niclas Håkansson; Per Hall; Emily Hallberg; Ute Hamann; Patricia Harrington; Alexander Hein; Belynda Hicks; Peter Hillemanns; Antoinette Hollestelle; Robert N. Hoover; John L. Hopper; Guanmengqian Huang; Keith Humphreys; David J. Hunter; Anna Jakubowska; Wolfgang Janni; Esther M. John; Nichola Johnson; Kristine Jones; Michael E. Jones; Audrey Jung; Rudolf Kaaks; Michael J. Kerin; Elza Khusnutdinova; Veli Matti Kosma; Vessela N. Kristensen; Diether Lambrechts; Loic Le Marchand; Jingmei Li; Sara Lindström; Jolanta Lissowska; Wing Yee Lo; Sibylle Loibl; Jan Lubinski; Craig Luccarini; Michael P. Lux; Robert J. MacInnis; Tom Maishman; Ivana Maleva Kostovska; Arto Mannermaa; Jo Ann E. Manson; Sara Margolin; Dimitrios Mavroudis; Hanne Meijers-Heijboer; Alfons Meindl; Usha Menon; Jeffery Meyer; Anna Marie Mulligan; Susan L. Neuhausen; Heli Nevanlinna; Patrick Neven; Sune F. Nielsen; Børge G. Nordestgaard; Olufunmilayo I. Olopade; Janet E. Olson; Håkan Olsson; Paolo Peterlongo; Julian Peto; Dijana Plaseska-Karanfilska; Ross Prentice; Nadege Presneau; Katri Pylkäs; Brigitte Rack; Paolo Radice; Nazneen Rahman; Gad Rennert; Hedy S. Rennert; Valerie Rhenius; Atocha Romero; Jane Romm; Anja Rudolph; Emmanouil Saloustros; Dale P. Sandler; Elinor J. Sawyer; Marjanka K. Schmidt; Rita K. Schmutzler; Andreas Schneeweiss; Rodney J. Scott; Christopher G. Scott; Sheila Seal; Mitul Shah; Martha J. Shrubsole; Ann Smeets; Melissa C. Southey; John J. Spinelli; Jennifer Stone; Harald Surowy; Anthony J. Swerdlow; Rulla M. Tamimi; William Tapper; Jack A. Taylor; Mary Beth Terry; Daniel C. Tessier; Abigail Thomas; Kathrin Thöne; Rob A.E.M. Tollenaar; Diana Torres; Thérèse Truong; Michael Untch; Celine Vachon; David Van Den Berg; Daniel Vincent; Quinten Waisfisz; Clarice R. Weinberg; Camilla Wendt; Alice S. Whittemore; Hans Wildiers; Walter C. Willett; Robert Winqvist; Alicja Wolk; Lucy Xia; Xiaohong R. Yang; Argyrios Ziogas; Elad Ziv; Alison M. Dunning; Paul D.P. Pharoah; Jacques Simard; Roger L. Milne; Stacey L. Edwards; Peter Kraft; Douglas F. Easton; Georgia Chenevix-Trench; Wei Zheng

doi:10.1038/s41588-018-0132-x

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Lang Wu, Wei Shi, Jirong Long, Xingyi Guo, Kyriaki Michailidou, Jonathan Beesley, Manjeet K. Bolla, Xiao Ou Shu, Yingchang Lu, Qiuyin Cai, Fares Al-Ejeh, Esdy Rozali, Qin Wang, Joe Dennis, Bingshan Li, Chenjie Zeng, Helian Feng, Alexander Gusev, Richard T. Barfield, Irene L. AndrulisHoda Anton-Culver, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Myrto Barrdahl, Caroline Baynes, Matthias W. Beckmann, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Hiltrud Brauch, Hermann Brenner, Louise Brinton, Per Broberg, Sara Y. Brucker, Barbara Burwinkel, Trinidad Caldés, Federico Canzian, Brian D. Carter, J. Esteban Castelao, Jenny Chang-Claude, Xiaoqing Chen, Ting Yuan David Cheng, Hans Christiansen, Christine L. Clarke, Margriet Collée, Sten Cornelissen, Fergus J. Couch, David Cox, Angela Cox, Simon S. Cross, Julie M. Cunningham, Kamila Czene, Mary B. Daly, Peter Devilee, Kimberly F. Doheny, Thilo Dörk, Isabel Dos-Santos-Silva, Martine Dumont, Miriam Dwek, Diana M. Eccles, Ursula Eilber, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, Laura Fachal, Peter A. Fasching, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Marike Gabrielson, Manuela Gago-Dominguez, Susan M. Gapstur, Montserrat García-Closas, Mia M. Gaudet, Maya Ghoussaini, Graham G. Giles, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Emily Hallberg, Ute Hamann, Patricia Harrington, Alexander Hein, Belynda Hicks, Peter Hillemanns, Antoinette Hollestelle, Robert N. Hoover, John L. Hopper, Guanmengqian Huang, Keith Humphreys, David J. Hunter, Anna Jakubowska, Wolfgang Janni, Esther M. John, Nichola Johnson, Kristine Jones, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Michael J. Kerin, Elza Khusnutdinova, Veli Matti Kosma, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Sara Lindström, Jolanta Lissowska, Wing Yee Lo, Sibylle Loibl, Jan Lubinski, Craig Luccarini, Michael P. Lux, Robert J. MacInnis, Tom Maishman, Ivana Maleva Kostovska, Arto Mannermaa, Jo Ann E. Manson, Sara Margolin, Dimitrios Mavroudis, Hanne Meijers-Heijboer, Alfons Meindl, Usha Menon, Jeffery Meyer, Anna Marie Mulligan, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Sune F. Nielsen, Børge G. Nordestgaard, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Paolo Peterlongo, Julian Peto, Dijana Plaseska-Karanfilska, Ross Prentice, Nadege Presneau, Katri Pylkäs, Brigitte Rack, Paolo Radice, Nazneen Rahman, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Jane Romm, Anja Rudolph, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Rodney J. Scott, Christopher G. Scott, Sheila Seal, Mitul Shah, Martha J. Shrubsole, Ann Smeets, Melissa C. Southey, John J. Spinelli, Jennifer Stone, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, William Tapper, Jack A. Taylor, Mary Beth Terry, Daniel C. Tessier, Abigail Thomas, Kathrin Thöne, Rob A.E.M. Tollenaar, Diana Torres, Thérèse Truong, Michael Untch, Celine Vachon, David Van Den Berg, Daniel Vincent, Quinten Waisfisz, Clarice R. Weinberg, Camilla Wendt, Alice S. Whittemore, Hans Wildiers, Walter C. Willett, Robert Winqvist, Alicja Wolk, Lucy Xia, Xiaohong R. Yang, Argyrios Ziogas, Elad Ziv, Alison M. Dunning, Paul D.P. Pharoah, Jacques Simard, Roger L. Milne, Stacey L. Edwards, Peter Kraft, Douglas F. Easton, Georgia Chenevix-Trench, Wei Zheng

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

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	https://doi.org/10.1038/s41588-018-0132-x
State	Published - Jul 1 2018

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/s41588-018-0132-x

Cite this

Wu, L., Shi, W., Long, J., Guo, X., Michailidou, K., Beesley, J., Bolla, M. K., Shu, X. O., Lu, Y., Cai, Q., Al-Ejeh, F., Rozali, E., Wang, Q., Dennis, J., Li, B., Zeng, C., Feng, H., Gusev, A., Barfield, R. T., ... Zheng, W. (2018). A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer. Nature Genetics, 50(7), 968-978. https://doi.org/10.1038/s41588-018-0132-x

Wu, L, Shi, W, Long, J, Guo, X, Michailidou, K, Beesley, J, Bolla, MK, Shu, XO, Lu, Y, Cai, Q, Al-Ejeh, F, Rozali, E, Wang, Q, Dennis, J, Li, B, Zeng, C, Feng, H, Gusev, A, Barfield, RT, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Barrdahl, M, Baynes, C, Beckmann, MW, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Brinton, L, Broberg, P, Brucker, SY, Burwinkel, B, Caldés, T, Canzian, F, Carter, BD, Castelao, JE, Chang-Claude, J, Chen, X, Cheng, TYD, Christiansen, H, Clarke, CL, Collée, M, Cornelissen, S, Couch, FJ, Cox, D, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Devilee, P, Doheny, KF, Dörk, T, Dos-Santos-Silva, I, Dumont, M, Dwek, M, Eccles, DM, Eilber, U, Eliassen, AH, Engel, C, Eriksson, M, Fachal, L, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gapstur, SM, García-Closas, M, Gaudet, MM, Ghoussaini, M, Giles, GG, Goldberg, MS, Goldgar, DE, González-Neira, A, Guénel, P, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hallberg, E, Hamann, U, Harrington, P, Hein, A, Hicks, B, Hillemanns, P, Hollestelle, A, Hoover, RN, Hopper, JL, Huang, G, Humphreys, K, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, K, Jones, ME, Jung, A, Kaaks, R, Kerin, MJ, Khusnutdinova, E, Kosma, VM, Kristensen, VN, Lambrechts, D, Le Marchand, L, Li, J, Lindström, S, Lissowska, J, Lo, WY, Loibl, S, Lubinski, J, Luccarini, C, Lux, MP, MacInnis, RJ, Maishman, T, Kostovska, IM, Mannermaa, A, Manson, JAE, Margolin, S, Mavroudis, D, Meijers-Heijboer, H, Meindl, A, Menon, U, Meyer, J, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Neven, P, Nielsen, SF, Nordestgaard, BG, Olopade, OI, Olson, JE, Olsson, H, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Prentice, R, Presneau, N, Pylkäs, K, Rack, B, Radice, P, Rahman, N, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Romm, J, Rudolph, A, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneeweiss, A, Scott, RJ, Scott, CG, Seal, S, Shah, M, Shrubsole, MJ, Smeets, A, Southey, MC, Spinelli, JJ, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, W, Taylor, JA, Terry, MB, Tessier, DC, Thomas, A, Thöne, K, Tollenaar, RAEM, Torres, D, Truong, T, Untch, M, Vachon, C, Van Den Berg, D, Vincent, D, Waisfisz, Q, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, WC, Winqvist, R, Wolk, A, Xia, L, Yang, XR, Ziogas, A, Ziv, E, Dunning, AM, Pharoah, PDP, Simard, J, Milne, RL, Edwards, SL, Kraft, P, Easton, DF, Chenevix-Trench, G & Zheng, W 2018, 'A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer', Nature Genetics, vol. 50, no. 7, pp. 968-978. https://doi.org/10.1038/s41588-018-0132-x

@article{0d09361f7e74499f8bf98416a927f290,

title = "A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer",

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.",

author = "Lang Wu and Wei Shi and Jirong Long and Xingyi Guo and Kyriaki Michailidou and Jonathan Beesley and Bolla, {Manjeet K.} and Shu, {Xiao Ou} and Yingchang Lu and Qiuyin Cai and Fares Al-Ejeh and Esdy Rozali and Qin Wang and Joe Dennis and Bingshan Li and Chenjie Zeng and Helian Feng and Alexander Gusev and Barfield, {Richard T.} and Andrulis, {Irene L.} and Hoda Anton-Culver and Volker Arndt and Aronson, {Kristan J.} and Auer, {Paul L.} and Myrto Barrdahl and Caroline Baynes and Beckmann, {Matthias W.} and Javier Benitez and Marina Bermisheva and Carl Blomqvist and Bogdanova, {Natalia V.} and Bojesen, {Stig E.} and Hiltrud Brauch and Hermann Brenner and Louise Brinton and Per Broberg and Brucker, {Sara Y.} and Barbara Burwinkel and Trinidad Cald{\'e}s and Federico Canzian and Carter, {Brian D.} and Castelao, {J. Esteban} and Jenny Chang-Claude and Xiaoqing Chen and Cheng, {Ting Yuan David} and Hans Christiansen and Clarke, {Christine L.} and Margriet Coll{\'e}e and Sten Cornelissen and Couch, {Fergus J.} and David Cox and Angela Cox and Cross, {Simon S.} and Cunningham, {Julie M.} and Kamila Czene and Daly, {Mary B.} and Peter Devilee and Doheny, {Kimberly F.} and Thilo D{\"o}rk and Isabel Dos-Santos-Silva and Martine Dumont and Miriam Dwek and Eccles, {Diana M.} and Ursula Eilber and Eliassen, {A. Heather} and Christoph Engel and Mikael Eriksson and Laura Fachal and Fasching, {Peter A.} and Jonine Figueroa and Dieter Flesch-Janys and Olivia Fletcher and Henrik Flyger and Lin Fritschi and Marike Gabrielson and Manuela Gago-Dominguez and Gapstur, {Susan M.} and Montserrat Garc{\'i}a-Closas and Gaudet, {Mia M.} and Maya Ghoussaini and Giles, {Graham G.} and Goldberg, {Mark S.} and Goldgar, {David E.} and Anna Gonz{\'a}lez-Neira and Pascal Gu{\'e}nel and Eric Hahnen and Haiman, {Christopher A.} and Niclas H{\aa}kansson and Per Hall and Emily Hallberg and Ute Hamann and Patricia Harrington and Alexander Hein and Belynda Hicks and Peter Hillemanns and Antoinette Hollestelle and Hoover, {Robert N.} and Hopper, {John L.} and Guanmengqian Huang and Keith Humphreys and Hunter, {David J.} and Anna Jakubowska and Wolfgang Janni and John, {Esther M.} and Nichola Johnson and Kristine Jones and Jones, {Michael E.} and Audrey Jung and Rudolf Kaaks and Kerin, {Michael J.} and Elza Khusnutdinova and Kosma, {Veli Matti} and Kristensen, {Vessela N.} and Diether Lambrechts and {Le Marchand}, Loic and Jingmei Li and Sara Lindstr{\"o}m and Jolanta Lissowska and Lo, {Wing Yee} and Sibylle Loibl and Jan Lubinski and Craig Luccarini and Lux, {Michael P.} and MacInnis, {Robert J.} and Tom Maishman and Kostovska, {Ivana Maleva} and Arto Mannermaa and Manson, {Jo Ann E.} and Sara Margolin and Dimitrios Mavroudis and Hanne Meijers-Heijboer and Alfons Meindl and Usha Menon and Jeffery Meyer and Mulligan, {Anna Marie} and Neuhausen, {Susan L.} and Heli Nevanlinna and Patrick Neven and Nielsen, {Sune F.} and Nordestgaard, {B{\o}rge G.} and Olopade, {Olufunmilayo I.} and Olson, {Janet E.} and H{\aa}kan Olsson and Paolo Peterlongo and Julian Peto and Dijana Plaseska-Karanfilska and Ross Prentice and Nadege Presneau and Katri Pylk{\"a}s and Brigitte Rack and Paolo Radice and Nazneen Rahman and Gad Rennert and Rennert, {Hedy S.} and Valerie Rhenius and Atocha Romero and Jane Romm and Anja Rudolph and Emmanouil Saloustros and Sandler, {Dale P.} and Sawyer, {Elinor J.} and Schmidt, {Marjanka K.} and Schmutzler, {Rita K.} and Andreas Schneeweiss and Scott, {Rodney J.} and Scott, {Christopher G.} and Sheila Seal and Mitul Shah and Shrubsole, {Martha J.} and Ann Smeets and Southey, {Melissa C.} and Spinelli, {John J.} and Jennifer Stone and Harald Surowy and Swerdlow, {Anthony J.} and Tamimi, {Rulla M.} and William Tapper and Taylor, {Jack A.} and Terry, {Mary Beth} and Tessier, {Daniel C.} and Abigail Thomas and Kathrin Th{\"o}ne and Tollenaar, {Rob A.E.M.} and Diana Torres and Th{\'e}r{\`e}se Truong and Michael Untch and Celine Vachon and {Van Den Berg}, David and Daniel Vincent and Quinten Waisfisz and Weinberg, {Clarice R.} and Camilla Wendt and Whittemore, {Alice S.} and Hans Wildiers and Willett, {Walter C.} and Robert Winqvist and Alicja Wolk and Lucy Xia and Yang, {Xiaohong R.} and Argyrios Ziogas and Elad Ziv and Dunning, {Alison M.} and Pharoah, {Paul D.P.} and Jacques Simard and Milne, {Roger L.} and Edwards, {Stacey L.} and Peter Kraft and Easton, {Douglas F.} and Georgia Chenevix-Trench and Wei Zheng",

note = "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 Minist{\`e}re de l{\textquoteright}{\'E}conomie, de la Science et de l{\textquoteright}Innovation du Qu{\'e}bec through Genome Qu{\'e}bec 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{\textquoteright}s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union{\textquoteright}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 {\textquoteleft}CIHR Team in Familial Risks of Breast Cancer{\textquoteright} 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: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = jul,

day = "1",

doi = "10.1038/s41588-018-0132-x",

language = "English (US)",

volume = "50",

pages = "968--978",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "7",

}

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

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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 -

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

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