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

Roger L Milne, Jesús Herranz, Kyriaki Michailidou, Joe Dennis, Jonathan P Tyrer, M Pilar Zamora, José Ignacio Arias-Perez, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Qin Wang, Manjeet K Bolla, Kamila Czene, Mikael Eriksson, Keith Humphreys, Hatef Darabi, Jingmei Li, Hoda Anton-Culver, Susan L Neuhausen, Argyrios ZiogasChristina A Clarke, John L Hopper, Gillian S Dite, Carmel Apicella, Melissa C Southey, Georgia Chenevix-Trench, Anthony Swerdlow, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Jonine D Figueroa, kConFab Investigators, Ian Tomlinson

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1934-46
Number of pages13
JournalHuman Molecular Genetics
Issue number7
Publication statusPublished - 1 Apr 2014


  • Breast Neoplasms
  • Case-Control Studies
  • Epistasis, Genetic
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Logistic Models
  • Polymorphism, Single Nucleotide

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