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
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
× corresponding author
# (joint) last author

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