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.
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2014
|
| _version_ | 1826259979261181952 |
|---|---|
| author | Milne, R Herranz, J Michailidou, K Dennis, J Tyrer, J Zamora, M Arias-Perez, J González-Neira, A Pita, G Alonso, MR Wang, Q Bolla, M Czene, K Eriksson, M Humphreys, K Darabi, H Li, J Anton-Culver, H Neuhausen, S Ziogas, A Clarke, C Hopper, J Dite, G Apicella, C Southey, M |
| author_facet | Milne, R Herranz, J Michailidou, K Dennis, J Tyrer, J Zamora, M Arias-Perez, J González-Neira, A Pita, G Alonso, MR Wang, Q Bolla, M Czene, K Eriksson, M Humphreys, K Darabi, H Li, J Anton-Culver, H Neuhausen, S Ziogas, A Clarke, C Hopper, J Dite, G Apicella, C Southey, M |
| author_sort | Milne, R |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T18:58:23Z |
| format | Journal article |
| id | oxford-uuid:12abda0c-8efa-4943-a018-0d33fa7982dd |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:58:23Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:12abda0c-8efa-4943-a018-0d33fa7982dd2022-03-26T10:09:09ZA 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 articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:12abda0c-8efa-4943-a018-0d33fa7982ddEnglishSymplectic Elements at Oxford2014Milne, RHerranz, JMichailidou, KDennis, JTyrer, JZamora, MArias-Perez, JGonzález-Neira, APita, GAlonso, MRWang, QBolla, MCzene, KEriksson, MHumphreys, KDarabi, HLi, JAnton-Culver, HNeuhausen, SZiogas, AClarke, CHopper, JDite, GApicella, CSouthey, MPart 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. |
| spellingShingle | Milne, R Herranz, J Michailidou, K Dennis, J Tyrer, J Zamora, M Arias-Perez, J González-Neira, A Pita, G Alonso, MR Wang, Q Bolla, M Czene, K Eriksson, M Humphreys, K Darabi, H Li, J Anton-Culver, H Neuhausen, S Ziogas, A Clarke, C Hopper, J Dite, G Apicella, C Southey, M 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. |
| 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | 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 |
| work_keys_str_mv | AT milner alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT herranzj alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT michailidouk alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT dennisj alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT tyrerj alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT zamoram alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT ariasperezj alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT gonzalezneiraa alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT pitag alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT alonsomr alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT wangq alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT bollam alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT czenek alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT erikssonm alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT humphreysk alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT darabih alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT lij alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT antonculverh alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT neuhausens alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT ziogasa alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT clarkec alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT hopperj alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT diteg alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT apicellac alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT southeym alargescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT milner largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT herranzj largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT michailidouk largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT dennisj largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT tyrerj largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT zamoram largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT ariasperezj largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT gonzalezneiraa largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT pitag largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT alonsomr largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT wangq largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT bollam largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT czenek largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT erikssonm largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT humphreysk largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT darabih largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT lij largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT antonculverh largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT neuhausens largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT ziogasa largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT clarkec largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT hopperj largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT diteg largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT apicellac largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium AT southeym largescaleassessmentoftwowaysnpinteractionsinbreastcancersusceptibilityusing46450casesand42461controlsfromthebreastcancerassociationconsortium |