Title: | A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium |
Authors: | Milne, Roger L × Herranz, Jesús Michailidou, Kyriaki Dennis, Joe Tyrer, Jonathan P Zamora, M Pilar Arias-Perez, José Ignacio González-Neira, Anna Pita, Guillermo Alonso, M Rosario Wang, Qin Bolla, Manjeet K Czene, Kamila Eriksson, Mikael Humphreys, Keith Darabi, Hatef Li, Jingmei Anton-Culver, Hoda Neuhausen, Susan L Ziogas, Argyrios Clarke, Christina A Hopper, John L Dite, Gillian S Apicella, Carmel Southey, Melissa C Chenevix-Trench, Georgia kConFab Investigators Australian Ovarian Cancer Study Group Swerdlow, Anthony Ashworth, Alan Orr, Nicholas Schoemaker, Minouk Jakubowska, Anna Lubinski, Jan Jaworska-Bieniek, Katarzyna Durda, Katarzyna Andrulis, Irene L Knight, Julia A Glendon, Gord Mulligan, Anna Marie Bojesen, Stig E Nordestgaard, Børge G Flyger, Henrik Nevanlinna, Heli Muranen, Taru A Aittomäki, Kristiina Blomqvist, Carl Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Wang, Xianshu Olson, Janet E Vachon, Celine Purrington, Kristen Winqvist, Robert Pylkäs, Katri Jukkola-Vuorinen, Arja Grip, Mervi Dunning, Alison M Shah, Mitul Guénel, Pascal Truong, Thérèse Sanchez, Marie Mulot, Claire Brenner, Hermann Dieffenbach, Aida Karina Arndt, Volker Stegmaier, Christa Lindblom, Annika Margolin, Sara Hooning, Maartje J Hollestelle, Antoinette Collée, J Margriet Jager, Agnes Cox, Angela Brock, Ian W Reed, Malcolm W R Devilee, Peter Tollenaar, Robert A E M Seynaeve, Caroline Haiman, Christopher A Henderson, Brian E Schumacher, Fredrick Le Marchand, Loic Simard, Jacques Dumont, Martine Soucy, Penny Dörk, Thilo Bogdanova, Natalia V Hamann, Ute Försti, Asta Rüdiger, Thomas Ulmer, Hans-Ulrich Fasching, Peter A Häberle, Lothar Ekici, Arif B Beckmann, Matthias W Fletcher, Olivia Johnson, Nichola Dos Santos Silva, Isabel Peto, Julian Radice, Paolo Peterlongo, Paolo Peissel, Bernard Mariani, Paolo Giles, Graham G Severi, Gianluca Baglietto, Laura Sawyer, Elinor Tomlinson, Ian Kerin, Michael Miller, Nicola Marme, Federik Burwinkel, Barbara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M Lambrechts, Diether Yesilyurt, Betul T Floris, Beppe Leunen, Karin Alnæs, Grethe Grenaker Kristensen, Vessela Børresen-Dale, Anne-Lise García-Closas, Montserrat Chanock, Stephen J Lissowska, Jolanta Figueroa, Jonine D Schmidt, Marjanka K Broeks, Annegien Verhoef, Senno Rutgers, Emiel J Brauch, Hiltrud Brüning, Thomas Ko, Yon-Dschun The GENICA Network Couch, Fergus J Toland, Amanda E The TNBCC Yannoukakos, Drakoulis Pharoah, Paul D P Hall, Per Benítez, Javier Malats, Núria Easton, Douglas F # |
Issue Date: | Apr-2014 |
Publisher: | IRL Press |
Series Title: | Human Molecular Genetics vol:23 issue:7 pages:1934-1946 |
Abstract: | Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10(-4)) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10(-8). Results from the second analytic approach were consistent with those from the first (P > 10(-10)). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome. |
ISSN: | 0964-6906 |
Publication status: | published |
KU Leuven publication type: | IT |
Appears in Collections: | Laboratory of Translational Genetics (VIB-KU Leuven Center for Cancer Biology) Translational Cell & Tissue Research Gynaecological Oncology
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