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Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes
Am J Hum Genet. 2019 Jan;104(1) :21-34
PMID: 30554720    PMCID: PMC6323553   
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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.
Notes
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 Aittomaki, Kristiina Allen, Jamie Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia N. Arndt, Volker Aronson, Kristan J. Auer, Paul L. Auvinen, Paivi Barrdahl, Myrto Freeman, Laura E. Beane Beckmann, Matthias W. Behrens, Sabine Benitez, Javier Bermisheva, Marina Bernstein, Leslie Blomqvist, Carl Bogdanova, Natalia, V Bojesen, Stig E. Bonanni, Bernardo Borresen-Dale, Anne-Lise Brauch, Hiltrud Bremer, Michael Brenner, Hermann Brentnall, Adam Brock, Ian W. Brooks-Wilson, Angela Brucker, Sara Y. Bruening, Thomas Burwinkel, Barbara Campa, Daniele Carter, Brian D. Castelao, Jose E. Chanock, Stephen J. Chlebowski, Rowan Christiansen, Hans Clarke, Christine L. Collee, J. Margriet Cordina-Duverger, Emilie Cornelissen, Sten Couch, Fergus J. Cox, Angela Cross, Simon S. Czene, Kamila Daly, Mary B. Devilee, Peter Doerk, 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 Foersti, Asta Fritschi, Lin Gabrielson, Marike Gago-Dominguez, Manuela Gapstur, Susan M. Garcia-Saenz, Jose A. Gaudet, Mia M. Georgoulias, Vassilios Giles, Graham G. Gilyazova, Irina R. Glendon, Gord Goldberg, Mark S. Goldgar, David E. Gonzalez-Neira, Anna Alnaes, Grethe I. Grenaker Grip, Mervi Gronwald, Jacek Grundy, Anne Guenel, Pascal Haeberle, Lothar Hahnen, Eric Haiman, Christopher A. Hakansson, 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. 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