Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Nasim Mavaddat, Kyriaki Michailidou, Joe Dennis, Michael Lush, Laura Fachal, Andrew Lee, Jonathan P. Tyrer, Ting Huei Chen, Qin Wang, Manjeet K. Bolla, Xin Yang, Muriel A. Adank, Thomas Ahearn, Kristiina Aittomäki, Jamie Allen, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson & 233 others Paul L. Auer, Päivi Auvinen, Myrto Barrdahl, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Anne Lise Børresen-Dale, Hiltrud Brauch, Michael Bremer, Hermann Brenner, Adam Brentnall, Ian W. Brock, NBCS Collaborators, ABCTB Investigators, kConFab/AOCS Investigators, Angela Brooks-Wilson, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Daniele Campa, Brian D. Carter, Jose E. Castelao, Stephen J. Chanock, Rowan Chlebowski, Hans Christiansen, Christine L. Clarke, J. Margriet Collée, Emilie Cordina-Duverger, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Isabel dos-Santos-Silva, Martine Dumont, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Olivia Fletcher, Henrik Flyger, Asta Försti, Lin Fritschi, Marike Gabrielson, Manuela Gago-Dominguez, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Irina R. Gilyazova, Gord Glendon, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Susan E. Hankinson, Elaine F. Harkness, Steven N. Hart, Wei He, Alexander Hein, Jane Heyworth, Peter Hillemanns, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Anthony Howell, Guanmengqian Huang, Keith Humphreys, David J. Hunter, Milena Jakimovska, Anna Jakubowska, Wolfgang Janni, Esther M. John, Nichola Johnson, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Katarzyna Kaczmarek, Vesa Kataja, Renske Keeman, Michael J. Kerin, Elza Khusnutdinova, Johanna I. Kiiski, Julia A. Knight, Yon Dschun Ko, Veli Matti Kosma, Stella Koutros, Vessela N. Kristensen, Ute Krüger, Tabea Kühl, Diether Lambrechts, Loic Le Marchand, Eunjung Lee, Flavio Lejbkowicz, Jenna Lilyquist, Annika Lindblom, Sara Lindström, Jolanta Lissowska, Wing Yee Lo, Sibylle Loibl, Jirong Long, Jan Lubiński, Michael P. Lux, Robert J. MacInnis, Tom Maishman, Enes Makalic, Ivana Maleva Kostovska, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W.M. Martens, Maria Elena Martinez, Dimitrios Mavroudis, Catriona McLean, Alfons Meindl, Usha Menon, Pooja Middha, Nicola Miller, Fernando Moreno, Anna Marie Mulligan, Claire Mulot, Victor M. Muñoz-Garzon, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Kenneth Offit, Janet E. Olson, Håkan Olsson, Nick Orr, V. Shane Pankratz, Tjoung Won Park-Simon, Jose I.A. Perez, Clara Pérez-Barrios, Paolo Peterlongo, Julian Peto, Mila Pinchev, Dijana Plaseska-Karanfilska, Eric C. Polley, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Kristen Purrington, Katri Pylkäs, Brigitte Rack, Paolo Radice, Rohini Rau-Murthy, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Mark Robson, Atocha Romero, Kathryn J. Ruddy, Matthias Ruebner, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Fredrick Schumacher, Peter Schürmann, Lukas Schwentner, Christopher Scott, Rodney J. Scott, Caroline Seynaeve, Mitul Shah, Mark E. Sherman, Martha J. Shrubsole, Xiao Ou Shu, Susan Slager, Ann Smeets, Christof Sohn, Penny Soucy, Melissa C. Southey, John J. Spinelli, Christa Stegmaier, Jennifer Stone, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Kathrin Thöne, Rob A.E.M. Tollenaar, Ian Tomlinson, Thérèse Truong, Maria Tzardi, Hans Ulrich Ulmer, Michael Untch, Celine M. Vachon, Elke M. van Veen, Joseph Vijai, Clarice R. Weinberg, Camilla Wendt, Alice S. Whittemore, Hans Wildiers, Walter Willett, Robert Winqvist, Roger L. Milne

Research output: Contribution to journalArticleResearchpeer-review

44 Citations (Scopus)

Abstract

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

Original languageEnglish
Pages (from-to)21-34
Number of pages14
JournalAmerican Journal of Human Genetics
Volume104
Issue number1
DOIs
Publication statusPublished - 3 Jan 2019

Keywords

  • breast
  • cancer
  • epidemiology
  • genetic
  • polygenic
  • prediction
  • risk
  • score
  • screening
  • stratification

Cite this

Mavaddat, Nasim ; Michailidou, Kyriaki ; Dennis, Joe ; Lush, Michael ; Fachal, Laura ; Lee, Andrew ; Tyrer, Jonathan P. ; Chen, Ting Huei ; Wang, Qin ; Bolla, Manjeet K. ; Yang, Xin ; Adank, Muriel A. ; Ahearn, Thomas ; Aittomäki, Kristiina ; Allen, Jamie ; Andrulis, Irene L. ; Anton-Culver, Hoda ; Antonenkova, Natalia N. ; Arndt, Volker ; Aronson, Kristan J. ; Auer, Paul L. ; Auvinen, Päivi ; Barrdahl, Myrto ; Beane Freeman, Laura E. ; Beckmann, Matthias W. ; Behrens, Sabine ; Benitez, Javier ; Bermisheva, Marina ; Bernstein, Leslie ; Blomqvist, Carl ; Bogdanova, Natalia V. ; Bojesen, Stig E. ; Bonanni, Bernardo ; Børresen-Dale, Anne Lise ; Brauch, Hiltrud ; Bremer, Michael ; Brenner, Hermann ; Brentnall, Adam ; Brock, Ian W. ; NBCS Collaborators ; ABCTB Investigators ; kConFab/AOCS Investigators ; Brooks-Wilson, Angela ; Brucker, Sara Y. ; Brüning, Thomas ; Burwinkel, Barbara ; Campa, Daniele ; Carter, Brian D. ; Castelao, Jose E. ; Chanock, Stephen J. ; Chlebowski, Rowan ; Christiansen, Hans ; Clarke, Christine L. ; Collée, J. Margriet ; Cordina-Duverger, Emilie ; Cornelissen, Sten ; Couch, Fergus J. ; Cox, Angela ; Cross, Simon S. ; Czene, Kamila ; Daly, Mary B. ; Devilee, Peter ; Dörk, Thilo ; dos-Santos-Silva, Isabel ; Dumont, Martine ; Durcan, Lorraine ; Dwek, Miriam ; Eccles, Diana M. ; Ekici, Arif B. ; Eliassen, A. Heather ; Ellberg, Carolina ; Engel, Christoph ; Eriksson, Mikael ; Evans, D. Gareth ; Fasching, Peter A. ; Figueroa, Jonine ; Fletcher, Olivia ; Flyger, Henrik ; Försti, Asta ; Fritschi, Lin ; Gabrielson, Marike ; Gago-Dominguez, Manuela ; Gapstur, Susan M. ; García-Sáenz, José A. ; Gaudet, Mia M. ; Georgoulias, Vassilios ; Giles, Graham G. ; Gilyazova, Irina R. ; Glendon, Gord ; Goldberg, Mark S. ; Goldgar, David E. ; González-Neira, Anna ; Grenaker Alnæs, Grethe I. ; Grip, Mervi ; Gronwald, Jacek ; Grundy, Anne ; Guénel, Pascal ; Haeberle, Lothar ; Hahnen, Eric ; Haiman, Christopher A. ; Håkansson, Niclas ; Hamann, Ute ; Hankinson, Susan E. ; Harkness, Elaine F. ; Hart, Steven N. ; He, Wei ; Hein, Alexander ; Heyworth, Jane ; Hillemanns, Peter ; Hollestelle, Antoinette ; Hooning, Maartje J. ; Hoover, Robert N. ; Hopper, John L. ; Howell, Anthony ; Huang, Guanmengqian ; Humphreys, Keith ; Hunter, David J. ; Jakimovska, Milena ; Jakubowska, Anna ; Janni, Wolfgang ; John, Esther M. ; Johnson, Nichola ; Jones, Michael E. ; Jukkola-Vuorinen, Arja ; Jung, Audrey ; Kaaks, Rudolf ; Kaczmarek, Katarzyna ; Kataja, Vesa ; Keeman, Renske ; Kerin, Michael J. ; Khusnutdinova, Elza ; Kiiski, Johanna I. ; Knight, Julia A. ; Ko, Yon Dschun ; Kosma, Veli Matti ; Koutros, Stella ; Kristensen, Vessela N. ; Krüger, Ute ; Kühl, Tabea ; Lambrechts, Diether ; Le Marchand, Loic ; Lee, Eunjung ; Lejbkowicz, Flavio ; Lilyquist, Jenna ; Lindblom, Annika ; Lindström, Sara ; Lissowska, Jolanta ; Lo, Wing Yee ; Loibl, Sibylle ; Long, Jirong ; Lubiński, Jan ; Lux, Michael P. ; MacInnis, Robert J. ; Maishman, Tom ; Makalic, Enes ; Maleva Kostovska, Ivana ; Mannermaa, Arto ; Manoukian, Siranoush ; Margolin, Sara ; Martens, John W.M. ; Martinez, Maria Elena ; Mavroudis, Dimitrios ; McLean, Catriona ; Meindl, Alfons ; Menon, Usha ; Middha, Pooja ; Miller, Nicola ; Moreno, Fernando ; Mulligan, Anna Marie ; Mulot, Claire ; Muñoz-Garzon, Victor M. ; Neuhausen, Susan L. ; Nevanlinna, Heli ; Neven, Patrick ; Newman, William G. ; Nielsen, Sune F. ; Nordestgaard, Børge G. ; Norman, Aaron ; Offit, Kenneth ; Olson, Janet E. ; Olsson, Håkan ; Orr, Nick ; Pankratz, V. Shane ; Park-Simon, Tjoung Won ; Perez, Jose I.A. ; Pérez-Barrios, Clara ; Peterlongo, Paolo ; Peto, Julian ; Pinchev, Mila ; Plaseska-Karanfilska, Dijana ; Polley, Eric C. ; Prentice, Ross ; Presneau, Nadege ; Prokofyeva, Darya ; Purrington, Kristen ; Pylkäs, Katri ; Rack, Brigitte ; Radice, Paolo ; Rau-Murthy, Rohini ; Rennert, Gad ; Rennert, Hedy S. ; Rhenius, Valerie ; Robson, Mark ; Romero, Atocha ; Ruddy, Kathryn J. ; Ruebner, Matthias ; Saloustros, Emmanouil ; Sandler, Dale P. ; Sawyer, Elinor J. ; Schmidt, Daniel F. ; Schmutzler, Rita K. ; Schneeweiss, Andreas ; Schoemaker, Minouk J. ; Schumacher, Fredrick ; Schürmann, Peter ; Schwentner, Lukas ; Scott, Christopher ; Scott, Rodney J. ; Seynaeve, Caroline ; Shah, Mitul ; Sherman, Mark E. ; Shrubsole, Martha J. ; Shu, Xiao Ou ; Slager, Susan ; Smeets, Ann ; Sohn, Christof ; Soucy, Penny ; Southey, Melissa C. ; Spinelli, John J. ; Stegmaier, Christa ; Stone, Jennifer ; Swerdlow, Anthony J. ; Tamimi, Rulla M. ; Tapper, William J. ; Taylor, Jack A. ; Terry, Mary Beth ; Thöne, Kathrin ; Tollenaar, Rob A.E.M. ; Tomlinson, Ian ; Truong, Thérèse ; Tzardi, Maria ; Ulmer, Hans Ulrich ; Untch, Michael ; Vachon, Celine M. ; van Veen, Elke M. ; Vijai, Joseph ; Weinberg, Clarice R. ; Wendt, Camilla ; Whittemore, Alice S. ; Wildiers, Hans ; Willett, Walter ; Winqvist, Robert ; Milne, Roger L. / Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes. In: American Journal of Human Genetics. 2019 ; Vol. 104, No. 1. pp. 21-34.
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title = "Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes",
abstract = "Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95{\%}CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95{\%}CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6{\%}. Compared with women in the middle quintile, those in the highest 1{\%} of risk had 4.37- and 2.78-fold risks, and those in the lowest 1{\%} of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.",
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author = "Nasim Mavaddat and Kyriaki Michailidou and Joe Dennis and Michael Lush and Laura Fachal and Andrew Lee and Tyrer, {Jonathan P.} and Chen, {Ting Huei} and Qin Wang and Bolla, {Manjeet K.} and Xin Yang and Adank, {Muriel A.} and Thomas Ahearn and Kristiina Aittom{\"a}ki and Jamie Allen and Andrulis, {Irene L.} and Hoda Anton-Culver and Antonenkova, {Natalia N.} and Volker Arndt and Aronson, {Kristan J.} and Auer, {Paul L.} and P{\"a}ivi Auvinen and Myrto Barrdahl and {Beane Freeman}, {Laura E.} and Beckmann, {Matthias W.} and Sabine Behrens and Javier Benitez and Marina Bermisheva and Leslie Bernstein and Carl Blomqvist and Bogdanova, {Natalia V.} and Bojesen, {Stig E.} and Bernardo Bonanni and B{\o}rresen-Dale, {Anne Lise} and Hiltrud Brauch and Michael Bremer and Hermann Brenner and Adam Brentnall and Brock, {Ian W.} and {NBCS Collaborators} and {ABCTB Investigators} and {kConFab/AOCS Investigators} and Angela Brooks-Wilson and Brucker, {Sara Y.} and Thomas Br{\"u}ning and Barbara Burwinkel and Daniele Campa and Carter, {Brian D.} and Castelao, {Jose E.} and Chanock, {Stephen J.} and Rowan Chlebowski and Hans Christiansen and Clarke, {Christine L.} and Coll{\'e}e, {J. Margriet} and Emilie Cordina-Duverger and Sten Cornelissen and Couch, {Fergus J.} and Angela Cox and Cross, {Simon S.} and Kamila Czene and Daly, {Mary B.} and Peter Devilee and Thilo D{\"o}rk and Isabel dos-Santos-Silva and Martine Dumont and Lorraine Durcan and Miriam Dwek and Eccles, {Diana M.} and Ekici, {Arif B.} and Eliassen, {A. Heather} and Carolina Ellberg and Christoph Engel and Mikael Eriksson and Evans, {D. Gareth} and Fasching, {Peter A.} and Jonine Figueroa and Olivia Fletcher and Henrik Flyger and Asta F{\"o}rsti and Lin Fritschi and Marike Gabrielson and Manuela Gago-Dominguez and Gapstur, {Susan M.} and Garc{\'i}a-S{\'a}enz, {Jos{\'e} A.} and Gaudet, {Mia M.} and Vassilios Georgoulias and Giles, {Graham G.} and Gilyazova, {Irina R.} and Gord Glendon and Goldberg, {Mark S.} and Goldgar, {David E.} and Anna Gonz{\'a}lez-Neira and {Grenaker Aln{\ae}s}, {Grethe I.} and Mervi Grip and Jacek Gronwald and Anne Grundy and Pascal Gu{\'e}nel and Lothar Haeberle and Eric Hahnen and Haiman, {Christopher A.} and Niclas H{\aa}kansson and Ute Hamann and Hankinson, {Susan E.} and Harkness, {Elaine F.} and Hart, {Steven N.} and Wei He and Alexander Hein and Jane Heyworth and Peter Hillemanns and Antoinette Hollestelle and Hooning, {Maartje J.} and Hoover, {Robert N.} and Hopper, {John L.} and Anthony Howell and Guanmengqian Huang and Keith Humphreys and Hunter, {David J.} and Milena Jakimovska and Anna Jakubowska and Wolfgang Janni and John, {Esther M.} and Nichola Johnson and Jones, {Michael E.} and Arja Jukkola-Vuorinen and Audrey Jung and Rudolf Kaaks and Katarzyna Kaczmarek and Vesa Kataja and Renske Keeman and Kerin, {Michael J.} and Elza Khusnutdinova and Kiiski, {Johanna I.} and Knight, {Julia A.} and Ko, {Yon Dschun} and Kosma, {Veli Matti} and Stella Koutros and Kristensen, {Vessela N.} and Ute Kr{\"u}ger and Tabea K{\"u}hl and Diether Lambrechts and {Le Marchand}, Loic and Eunjung Lee and Flavio Lejbkowicz and Jenna Lilyquist and Annika Lindblom and Sara Lindstr{\"o}m and Jolanta Lissowska and Lo, {Wing Yee} and Sibylle Loibl and Jirong Long and Jan Lubiński and Lux, {Michael P.} and MacInnis, {Robert J.} and Tom Maishman and Enes Makalic and {Maleva Kostovska}, Ivana and Arto Mannermaa and Siranoush Manoukian and Sara Margolin and Martens, {John W.M.} and Martinez, {Maria Elena} and Dimitrios Mavroudis and Catriona McLean and Alfons Meindl and Usha Menon and Pooja Middha and Nicola Miller and Fernando Moreno and Mulligan, {Anna Marie} and Claire Mulot and Mu{\~n}oz-Garzon, {Victor M.} and Neuhausen, {Susan L.} and Heli Nevanlinna and Patrick Neven and Newman, {William G.} and Nielsen, {Sune F.} and Nordestgaard, {B{\o}rge G.} and Aaron Norman and Kenneth Offit and Olson, {Janet E.} and H{\aa}kan Olsson and Nick Orr and Pankratz, {V. Shane} and Park-Simon, {Tjoung Won} and Perez, {Jose I.A.} and Clara P{\'e}rez-Barrios and Paolo Peterlongo and Julian Peto and Mila Pinchev and Dijana Plaseska-Karanfilska and Polley, {Eric C.} and Ross Prentice and Nadege Presneau and Darya Prokofyeva and Kristen Purrington and Katri Pylk{\"a}s and Brigitte Rack and Paolo Radice and Rohini Rau-Murthy and Gad Rennert and Rennert, {Hedy S.} and Valerie Rhenius and Mark Robson and Atocha Romero and Ruddy, {Kathryn J.} and Matthias Ruebner and Emmanouil Saloustros and Sandler, {Dale P.} and Sawyer, {Elinor J.} and Schmidt, {Daniel F.} and Schmutzler, {Rita K.} and Andreas Schneeweiss and Schoemaker, {Minouk J.} and Fredrick Schumacher and Peter Sch{\"u}rmann and Lukas Schwentner and Christopher Scott and Scott, {Rodney J.} and Caroline Seynaeve and Mitul Shah and Sherman, {Mark E.} and Shrubsole, {Martha J.} and Shu, {Xiao Ou} and Susan Slager and Ann Smeets and Christof Sohn and Penny Soucy and Southey, {Melissa C.} and Spinelli, {John J.} and Christa Stegmaier and Jennifer Stone and Swerdlow, {Anthony J.} and Tamimi, {Rulla M.} and Tapper, {William J.} and Taylor, {Jack A.} and Terry, {Mary Beth} and Kathrin Th{\"o}ne and Tollenaar, {Rob A.E.M.} and Ian Tomlinson and Th{\'e}r{\`e}se Truong and Maria Tzardi and Ulmer, {Hans Ulrich} and Michael Untch and Vachon, {Celine M.} and {van Veen}, {Elke M.} and Joseph Vijai and Weinberg, {Clarice R.} and Camilla Wendt and Whittemore, {Alice S.} and Hans Wildiers and Walter Willett and Robert Winqvist and Milne, {Roger L.}",
year = "2019",
month = "1",
day = "3",
doi = "10.1016/j.ajhg.2018.11.002",
language = "English",
volume = "104",
pages = "21--34",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",

}

Mavaddat, N, Michailidou, K, Dennis, J, Lush, M, Fachal, L, Lee, A, Tyrer, JP, Chen, TH, Wang, Q, Bolla, MK, Yang, X, Adank, MA, Ahearn, T, Aittomäki, K, Allen, J, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Auer, PL, Auvinen, P, Barrdahl, M, Beane Freeman, LE, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Børresen-Dale, AL, Brauch, H, Bremer, M, Brenner, H, Brentnall, A, Brock, IW, NBCS Collaborators, ABCTB Investigators, kConFab/AOCS Investigators, Brooks-Wilson, A, Brucker, SY, Brüning, T, Burwinkel, B, Campa, D, Carter, BD, Castelao, JE, Chanock, SJ, Chlebowski, R, Christiansen, H, Clarke, CL, Collée, JM, Cordina-Duverger, E, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dörk, T, dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Försti, A, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gapstur, SM, García-Sáenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Gilyazova, IR, Glendon, G, Goldberg, MS, Goldgar, DE, González-Neira, A, Grenaker Alnæs, GI, Grip, M, Gronwald, J, Grundy, A, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hankinson, SE, Harkness, EF, Hart, SN, He, W, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Jakimovska, M, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kaczmarek, K, Kataja, V, Keeman, R, Kerin, MJ, Khusnutdinova, E, Kiiski, JI, Knight, JA, Ko, YD, Kosma, VM, Koutros, S, Kristensen, VN, Krüger, U, Kühl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Lilyquist, J, Lindblom, A, Lindström, S, Lissowska, J, Lo, WY, Loibl, S, Long, J, Lubiński, J, Lux, MP, MacInnis, RJ, Maishman, T, Makalic, E, Maleva Kostovska, I, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Menon, U, Middha, P, Miller, N, Moreno, F, Mulligan, AM, Mulot, C, Muñoz-Garzon, VM, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsen, SF, Nordestgaard, BG, Norman, A, Offit, K, Olson, JE, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, TW, Perez, JIA, Pérez-Barrios, C, Peterlongo, P, Peto, J, Pinchev, M, Plaseska-Karanfilska, D, Polley, EC, Prentice, R, Presneau, N, Prokofyeva, D, Purrington, K, Pylkäs, K, Rack, B, Radice, P, Rau-Murthy, R, Rennert, G, Rennert, HS, Rhenius, V, Robson, M, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schürmann, P, Schwentner, L, Scott, C, Scott, RJ, Seynaeve, C, Shah, M, Sherman, ME, Shrubsole, MJ, Shu, XO, Slager, S, Smeets, A, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Stegmaier, C, Stone, J, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Thöne, K, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tzardi, M, Ulmer, HU, Untch, M, Vachon, CM, van Veen, EM, Vijai, J, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R & Milne, RL 2019, 'Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes', American Journal of Human Genetics, vol. 104, no. 1, pp. 21-34. https://doi.org/10.1016/j.ajhg.2018.11.002

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes. / Mavaddat, Nasim; Michailidou, Kyriaki; Dennis, Joe; Lush, Michael; Fachal, Laura; Lee, Andrew; Tyrer, Jonathan P.; Chen, Ting Huei; Wang, Qin; Bolla, Manjeet K.; Yang, Xin; Adank, Muriel A.; Ahearn, Thomas; Aittomäki, Kristiina; Allen, Jamie; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; Aronson, Kristan J.; Auer, Paul L.; Auvinen, Päivi; Barrdahl, Myrto; Beane Freeman, Laura E.; Beckmann, Matthias W.; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bonanni, Bernardo; Børresen-Dale, Anne Lise; Brauch, Hiltrud; Bremer, Michael; Brenner, Hermann; Brentnall, Adam; Brock, Ian W.; NBCS Collaborators; ABCTB Investigators; kConFab/AOCS Investigators; Brooks-Wilson, Angela; Brucker, Sara Y.; Brüning, Thomas; Burwinkel, Barbara; Campa, Daniele; Carter, Brian D.; Castelao, Jose E.; Chanock, Stephen J.; Chlebowski, Rowan; Christiansen, Hans; Clarke, Christine L.; Collée, J. Margriet; Cordina-Duverger, Emilie; Cornelissen, Sten; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Dörk, Thilo; dos-Santos-Silva, Isabel; Dumont, Martine; Durcan, Lorraine; Dwek, Miriam; Eccles, Diana M.; Ekici, Arif B.; Eliassen, A. Heather; Ellberg, Carolina; Engel, Christoph; Eriksson, Mikael; Evans, D. Gareth; Fasching, Peter A.; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Försti, Asta; Fritschi, Lin; Gabrielson, Marike; Gago-Dominguez, Manuela; Gapstur, Susan M.; García-Sáenz, José A.; Gaudet, Mia M.; Georgoulias, Vassilios; Giles, Graham G.; Gilyazova, Irina R.; Glendon, Gord; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Grenaker Alnæs, Grethe I.; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Guénel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hamann, Ute; Hankinson, Susan E.; Harkness, Elaine F.; Hart, Steven N.; He, Wei; Hein, Alexander; Heyworth, Jane; Hillemanns, Peter; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Howell, Anthony; Huang, Guanmengqian; Humphreys, Keith; Hunter, David J.; Jakimovska, Milena; Jakubowska, Anna; Janni, Wolfgang; John, Esther M.; Johnson, Nichola; Jones, Michael E.; Jukkola-Vuorinen, Arja; Jung, Audrey; Kaaks, Rudolf; Kaczmarek, Katarzyna; Kataja, Vesa; Keeman, Renske; Kerin, Michael J.; Khusnutdinova, Elza; Kiiski, Johanna I.; Knight, Julia A.; Ko, Yon Dschun; Kosma, Veli Matti; Koutros, Stella; Kristensen, Vessela N.; Krüger, Ute; Kühl, Tabea; Lambrechts, Diether; Le Marchand, Loic; Lee, Eunjung; Lejbkowicz, Flavio; Lilyquist, Jenna; Lindblom, Annika; Lindström, Sara; Lissowska, Jolanta; Lo, Wing Yee; Loibl, Sibylle; Long, Jirong; Lubiński, Jan; Lux, Michael P.; MacInnis, Robert J.; Maishman, Tom; Makalic, Enes; Maleva Kostovska, Ivana; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Martens, John W.M.; Martinez, Maria Elena; Mavroudis, Dimitrios; McLean, Catriona; Meindl, Alfons; Menon, Usha; Middha, Pooja; Miller, Nicola; Moreno, Fernando; Mulligan, Anna Marie; Mulot, Claire; Muñoz-Garzon, Victor M.; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Newman, William G.; Nielsen, Sune F.; Nordestgaard, Børge G.; Norman, Aaron; Offit, Kenneth; Olson, Janet E.; Olsson, Håkan; Orr, Nick; Pankratz, V. Shane; Park-Simon, Tjoung Won; Perez, Jose I.A.; Pérez-Barrios, Clara; Peterlongo, Paolo; Peto, Julian; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Polley, Eric C.; Prentice, Ross; Presneau, Nadege; Prokofyeva, Darya; Purrington, Kristen; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rau-Murthy, Rohini; Rennert, Gad; Rennert, Hedy S.; Rhenius, Valerie; Robson, Mark; Romero, Atocha; Ruddy, Kathryn J.; Ruebner, Matthias; Saloustros, Emmanouil; Sandler, Dale P.; Sawyer, Elinor J.; Schmidt, Daniel F.; Schmutzler, Rita K.; Schneeweiss, Andreas; Schoemaker, Minouk J.; Schumacher, Fredrick; Schürmann, Peter; Schwentner, Lukas; Scott, Christopher; Scott, Rodney J.; Seynaeve, Caroline; Shah, Mitul; Sherman, Mark E.; Shrubsole, Martha J.; Shu, Xiao Ou; Slager, Susan; Smeets, Ann; Sohn, Christof; Soucy, Penny; Southey, Melissa C.; Spinelli, John J.; Stegmaier, Christa; Stone, Jennifer; Swerdlow, Anthony J.; Tamimi, Rulla M.; Tapper, William J.; Taylor, Jack A.; Terry, Mary Beth; Thöne, Kathrin; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Truong, Thérèse; Tzardi, Maria; Ulmer, Hans Ulrich; Untch, Michael; Vachon, Celine M.; van Veen, Elke M.; Vijai, Joseph; Weinberg, Clarice R.; Wendt, Camilla; Whittemore, Alice S.; Wildiers, Hans; Willett, Walter; Winqvist, Robert; Milne, Roger L.

In: American Journal of Human Genetics, Vol. 104, No. 1, 03.01.2019, p. 21-34.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

AU - Mavaddat, Nasim

AU - Michailidou, Kyriaki

AU - Dennis, Joe

AU - Lush, Michael

AU - Fachal, Laura

AU - Lee, Andrew

AU - Tyrer, Jonathan P.

AU - Chen, Ting Huei

AU - Wang, Qin

AU - Bolla, Manjeet K.

AU - Yang, Xin

AU - Adank, Muriel A.

AU - Ahearn, Thomas

AU - Aittomäki, Kristiina

AU - Allen, Jamie

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia N.

AU - Arndt, Volker

AU - Aronson, Kristan J.

AU - Auer, Paul L.

AU - Auvinen, Päivi

AU - Barrdahl, Myrto

AU - Beane Freeman, Laura E.

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Bernstein, Leslie

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Bonanni, Bernardo

AU - Børresen-Dale, Anne Lise

AU - Brauch, Hiltrud

AU - Bremer, Michael

AU - Brenner, Hermann

AU - Brentnall, Adam

AU - Brock, Ian W.

AU - NBCS Collaborators

AU - ABCTB Investigators

AU - kConFab/AOCS Investigators

AU - Brooks-Wilson, Angela

AU - Brucker, Sara Y.

AU - Brüning, Thomas

AU - Burwinkel, Barbara

AU - Campa, Daniele

AU - Carter, Brian D.

AU - Castelao, Jose E.

AU - Chanock, Stephen J.

AU - Chlebowski, Rowan

AU - Christiansen, Hans

AU - Clarke, Christine L.

AU - Collée, J. Margriet

AU - Cordina-Duverger, Emilie

AU - Cornelissen, Sten

AU - Couch, Fergus J.

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Daly, Mary B.

AU - Devilee, Peter

AU - Dörk, Thilo

AU - dos-Santos-Silva, Isabel

AU - Dumont, Martine

AU - Durcan, Lorraine

AU - Dwek, Miriam

AU - Eccles, Diana M.

AU - Ekici, Arif B.

AU - Eliassen, A. Heather

AU - Ellberg, Carolina

AU - Engel, Christoph

AU - Eriksson, Mikael

AU - Evans, D. Gareth

AU - Fasching, Peter A.

AU - Figueroa, Jonine

AU - Fletcher, Olivia

AU - Flyger, Henrik

AU - Försti, Asta

AU - Fritschi, Lin

AU - Gabrielson, Marike

AU - Gago-Dominguez, Manuela

AU - Gapstur, Susan M.

AU - García-Sáenz, José A.

AU - Gaudet, Mia M.

AU - Georgoulias, Vassilios

AU - Giles, Graham G.

AU - Gilyazova, Irina R.

AU - Glendon, Gord

AU - Goldberg, Mark S.

AU - Goldgar, David E.

AU - González-Neira, Anna

AU - Grenaker Alnæs, Grethe I.

AU - Grip, Mervi

AU - Gronwald, Jacek

AU - Grundy, Anne

AU - Guénel, Pascal

AU - Haeberle, Lothar

AU - Hahnen, Eric

AU - Haiman, Christopher A.

AU - Håkansson, Niclas

AU - Hamann, Ute

AU - Hankinson, Susan E.

AU - Harkness, Elaine F.

AU - Hart, Steven N.

AU - He, Wei

AU - Hein, Alexander

AU - Heyworth, Jane

AU - Hillemanns, Peter

AU - Hollestelle, Antoinette

AU - Hooning, Maartje J.

AU - Hoover, Robert N.

AU - Hopper, John L.

AU - Howell, Anthony

AU - Huang, Guanmengqian

AU - Humphreys, Keith

AU - Hunter, David J.

AU - Jakimovska, Milena

AU - Jakubowska, Anna

AU - Janni, Wolfgang

AU - John, Esther M.

AU - Johnson, Nichola

AU - Jones, Michael E.

AU - Jukkola-Vuorinen, Arja

AU - Jung, Audrey

AU - Kaaks, Rudolf

AU - Kaczmarek, Katarzyna

AU - Kataja, Vesa

AU - Keeman, Renske

AU - Kerin, Michael J.

AU - Khusnutdinova, Elza

AU - Kiiski, Johanna I.

AU - Knight, Julia A.

AU - Ko, Yon Dschun

AU - Kosma, Veli Matti

AU - Koutros, Stella

AU - Kristensen, Vessela N.

AU - Krüger, Ute

AU - Kühl, Tabea

AU - Lambrechts, Diether

AU - Le Marchand, Loic

AU - Lee, Eunjung

AU - Lejbkowicz, Flavio

AU - Lilyquist, Jenna

AU - Lindblom, Annika

AU - Lindström, Sara

AU - Lissowska, Jolanta

AU - Lo, Wing Yee

AU - Loibl, Sibylle

AU - Long, Jirong

AU - Lubiński, Jan

AU - Lux, Michael P.

AU - MacInnis, Robert J.

AU - Maishman, Tom

AU - Makalic, Enes

AU - Maleva Kostovska, Ivana

AU - Mannermaa, Arto

AU - Manoukian, Siranoush

AU - Margolin, Sara

AU - Martens, John W.M.

AU - Martinez, Maria Elena

AU - Mavroudis, Dimitrios

AU - McLean, Catriona

AU - Meindl, Alfons

AU - Menon, Usha

AU - Middha, Pooja

AU - Miller, Nicola

AU - Moreno, Fernando

AU - Mulligan, Anna Marie

AU - Mulot, Claire

AU - Muñoz-Garzon, Victor M.

AU - Neuhausen, Susan L.

AU - Nevanlinna, Heli

AU - Neven, Patrick

AU - Newman, William G.

AU - Nielsen, Sune F.

AU - Nordestgaard, Børge G.

AU - Norman, Aaron

AU - Offit, Kenneth

AU - Olson, Janet E.

AU - Olsson, Håkan

AU - Orr, Nick

AU - Pankratz, V. Shane

AU - Park-Simon, Tjoung Won

AU - Perez, Jose I.A.

AU - Pérez-Barrios, Clara

AU - Peterlongo, Paolo

AU - Peto, Julian

AU - Pinchev, Mila

AU - Plaseska-Karanfilska, Dijana

AU - Polley, Eric C.

AU - Prentice, Ross

AU - Presneau, Nadege

AU - Prokofyeva, Darya

AU - Purrington, Kristen

AU - Pylkäs, Katri

AU - Rack, Brigitte

AU - Radice, Paolo

AU - Rau-Murthy, Rohini

AU - Rennert, Gad

AU - Rennert, Hedy S.

AU - Rhenius, Valerie

AU - Robson, Mark

AU - Romero, Atocha

AU - Ruddy, Kathryn J.

AU - Ruebner, Matthias

AU - Saloustros, Emmanouil

AU - Sandler, Dale P.

AU - Sawyer, Elinor J.

AU - Schmidt, Daniel F.

AU - Schmutzler, Rita K.

AU - Schneeweiss, Andreas

AU - Schoemaker, Minouk J.

AU - Schumacher, Fredrick

AU - Schürmann, Peter

AU - Schwentner, Lukas

AU - Scott, Christopher

AU - Scott, Rodney J.

AU - Seynaeve, Caroline

AU - Shah, Mitul

AU - Sherman, Mark E.

AU - Shrubsole, Martha J.

AU - Shu, Xiao Ou

AU - Slager, Susan

AU - Smeets, Ann

AU - Sohn, Christof

AU - Soucy, Penny

AU - Southey, Melissa C.

AU - Spinelli, John J.

AU - Stegmaier, Christa

AU - Stone, Jennifer

AU - Swerdlow, Anthony J.

AU - Tamimi, Rulla M.

AU - Tapper, William J.

AU - Taylor, Jack A.

AU - Terry, Mary Beth

AU - Thöne, Kathrin

AU - Tollenaar, Rob A.E.M.

AU - Tomlinson, Ian

AU - Truong, Thérèse

AU - Tzardi, Maria

AU - Ulmer, Hans Ulrich

AU - Untch, Michael

AU - Vachon, Celine M.

AU - van Veen, Elke M.

AU - Vijai, Joseph

AU - Weinberg, Clarice R.

AU - Wendt, Camilla

AU - Whittemore, Alice S.

AU - Wildiers, Hans

AU - Willett, Walter

AU - Winqvist, Robert

AU - Milne, Roger L.

PY - 2019/1/3

Y1 - 2019/1/3

N2 - Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

AB - Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

KW - breast

KW - cancer

KW - epidemiology

KW - genetic

KW - polygenic

KW - prediction

KW - risk

KW - score

KW - screening

KW - stratification

UR - http://www.scopus.com/inward/record.url?scp=85059498503&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2018.11.002

DO - 10.1016/j.ajhg.2018.11.002

M3 - Article

VL - 104

SP - 21

EP - 34

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -