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

Journal article

Publication Details

Author(s): Milne RL, Herranz J, Michailidou K, Dennis J, Tyrer JP, Zamora MP, Arias-Perez JI, Gonzalez-Neira A, Pita G, Alonso MR, Wang Q, Bolla MK, Czene K, Eriksson M, Humphreys K, Darabi H, Li J, Anton-Culver H, Neuhausen SL, Ziogas A, Clarke CA, Hopper JL, Dite GS, Apicella C, Southey MC, Chenevix-Trench G, Swerdlow A, Ashworth A, Orr N, Schoemaker M, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Andrulism IL, Knight JA, Glendon G, Mulligan AM, Bojesen SE, Nordestgaard BG, Flyger H, Nevanlinna HL, Muranen TA, Aittomaki K, Blomqvist C, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Wang X, Olson JE, Vachon C, Purrington K, Winqvist R, Pylkas K, Jukkola-Vuorinen A, Grip M, Dunning AM, Shah M, Guenel P, Truong T, Sanchez M, Mulot C, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Lindblom A, Margolin S, Hooning MJ, Hollestelle A, Collee JM, Jager A, Cox A, Brock IW, Reed MWR, Devilee P, Tollenaar RAEM, Seynaeve C, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Dumont M, Soucy P, Doerk T, Bogdanova NV, Hamann U, Foersti A, Ruediger T, Ulmer HU, Fasching P, Häberle L, Ekici AB, Beckmann M, Fletcher O, Johnson N, Silva IDS, Peto J, Radice P, Peterlongo P, Peissel B, Mariani P, Giles GG, Severi G, Baglietto L, Sawyer E, Tomlinson I, Kerin M, Miller N, Marme F, Burwinkei B, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Lambrechts D, Yesilyurt BT, Floris G, Leunen K, Alnaes GG, Kristensen V, Borresen-Dale AL, Garcia-Closas M, Chanock SJ, Lissowska J, Figueroa JD, Schmidt MK, Broeks A, Verhoef S, Rutgers EJ, Brauch H, Bruening T, Ko YD, Couch FJ, Toland AE, Yannoukakos D, Pharoah PDP, Hall P, Benitez J, Malats N, Easton DF
Journal: Human Molecular Genetics
Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B
Publication year: 2014
Volume: 23
Journal issue: 7
Pages range: 1934-46
ISSN: 0964-6906


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.

FAU Authors / FAU Editors

Beckmann, Matthias Prof. Dr.
Lehrstuhl für Geburtshilfe und Frauenheilkunde
Ekici, Arif Bülent Dr. rer. nat.
Humangenetisches Institut
Fasching, Peter PD Dr.
Professur für Translationale Frauenheilkunde und Geburtshilfe

External institutions with authors

Antoni van Leeuwenhoek
Cancer Prevention Institute of California (CPIC)
Centre de Ressources Biologiques (CRB EPIGENETEC)
City of Hope Medical Center
Deutsches Krebsforschungszentrum (DKFZ)
Eberhard Karls Universität Tübingen
Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam
Fondazione IRCCS: Istituto Nazionale dei Tumori
Genome Institute of Singapore
Guy's and St Thomas'
Helsingin yliopisto / University of Helsinki
Hospital Monte Naranco
Hospital Universitario La Paz
IFOM - FIRC Institute of Molecular Oncology
Institut für Prävention und Arbeitsmedizin der Deutschen Gesetzlichen Unfallversicherung (IPA)
Karolinska Institute
Klinikum Mittelbaden Baden-Baden Balg
Krebsregister Saarland / Saarland Cancer Registry
Kuopio University Hospital / Pohjois-Savon sairaanhoitopiiri
Leiden University
London School of Hygiene and Tropical Medicine
Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie
Mayo Clinic
Medizinische Hochschule Hannover (MHH) / Hannover Medical School
Mount Sinai Hospital (MSH)
National Cancer Institute (NCI)
National Centre for Scientific Research (NCSR) "Demokritos"
National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM)
National University of Ireland (NUI), Galway
Ohio State University
Ontario Cancer Genetics Network
Oslo University Hospital / Oslo Universitetssykehus
Oulun Yliopisto / University of Oulo
Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU)
QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research)
Ruprecht-Karls-Universität Heidelberg
Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO)
Städtisches Klinikum Karlsruhe
The University of Melbourne
Universitätsklinikum Hamburg-Eppendorf (UKE)
University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven
University of California Irvine
University of Cambridge
University of Copenhagen
University of Hawaii (U.H.)
University of Oxford
University of Sheffield
University of Southern California (USC)
University of Toronto

How to cite

Milne, R.L., Herranz, J., Michailidou, K., Dennis, J., Tyrer, J.P., Zamora, M.P.,... Easton, D.F. (2014). 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. Human Molecular Genetics, 23(7), 1934-46. https://dx.doi.org/10.1093/hmg/ddt581

Milne, Roger L., et al. "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." Human Molecular Genetics 23.7 (2014): 1934-46.


Last updated on 2019-21-07 at 07:59