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

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 (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B

Book Volume: 23

Pages Range: 1934-46

Journal Issue: 7

DOI: 10.1093/hmg/ddt581

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.

Authors with CRIS profile

Involved external institutions

Krebsregister Saarland / Saarland Cancer Registry Germany (DE) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) University of Cambridge United Kingdom (GB) Hospital Universitario La Paz Spain (ES) Hospital Monte Naranco Spain (ES) Karolinska Institute Sweden (SE) City of Hope Medical Center United States (USA) (US) Cancer Prevention Institute of California (CPIC) United States (USA) (US) The University of Melbourne Australia (AU) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Mount Sinai Hospital (MSH) Canada (CA) Ontario Cancer Genetics Network Canada (CA) University of Toronto Canada (CA) University of Copenhagen Denmark (DK) Helsingin yliopisto / University of Helsinki Finland (FI) Mayo Clinic United States (USA) (US) Oulun Yliopisto / University of Oulo Finland (FI) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) Centre de Ressources Biologiques (CRB EPIGENETEC) France (FR) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam Netherlands (NL) University of Sheffield United Kingdom (GB) Leiden University Netherlands (NL) University of Southern California (USC) United States (USA) (US) University of Hawaii (U.H.) United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Städtisches Klinikum Karlsruhe Germany (DE) London School of Hygiene and Tropical Medicine United Kingdom (GB) Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) IFOM - FIRC Institute of Molecular Oncology Italy (IT) Guy's and St Thomas' (NHS Foundation Trust) United Kingdom (GB) University of Oxford United Kingdom (GB) National University of Ireland (NUI), Galway Ireland (IE) Ruprecht-Karls-Universität Heidelberg Germany (DE) Kuopio University Hospital / Pohjois-Savon sairaanhoitopiiri Finland (FI) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) National Cancer Institute (NCI) United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Antoni van Leeuwenhoek Netherlands (NL) Institut für Prävention und Arbeitsmedizin der Deutschen Gesetzlichen Unfallversicherung (IPA) Germany (DE) Ohio State University United States (USA) (US) University of California Irvine United States (USA) (US) National Centre for Scientific Research (NCSR) "Demokritos" Greece (GR) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Klinikum Mittelbaden Baden-Baden Balg Germany (DE) Eberhard Karls Universität Tübingen Germany (DE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Genome Institute of Singapore Singapore (SG)

How to cite

APA:

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://doi.org/10.1093/hmg/ddt581

MLA:

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.

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