TY - JOUR
T1 - 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
AU - Milne, Roger L
AU - Herranz, Jesús
AU - Michailidou, Kyriaki
AU - Dennis, Joe
AU - Tyrer, Jonathan P
AU - Zamora, M Pilar
AU - Arias-Perez, José Ignacio
AU - González-Neira, Anna
AU - Pita, Guillermo
AU - Alonso, M Rosario
AU - Wang, Qin
AU - Bolla, Manjeet K
AU - Czene, Kamila
AU - Eriksson, Mikael
AU - Humphreys, Keith
AU - Darabi, Hatef
AU - Li, Jingmei
AU - Anton-Culver, Hoda
AU - Neuhausen, Susan L
AU - Ziogas, Argyrios
AU - Clarke, Christina A
AU - Hopper, John L
AU - Dite, Gillian S
AU - Apicella, Carmel
AU - Southey, Melissa C
AU - Chenevix-Trench, Georgia
AU - Swerdlow, Anthony
AU - Ashworth, Alan
AU - Orr, Nicholas
AU - Schoemaker, Minouk
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Jaworska-Bieniek, Katarzyna
AU - Durda, Katarzyna
AU - Andrulis, Irene L
AU - Knight, Julia A
AU - Glendon, Gord
AU - Mulligan, Anna Marie
AU - Bojesen, Stig E
AU - Nordestgaard, Børge G
AU - Flyger, Henrik
AU - Nevanlinna, Heli
AU - Muranen, Taru A
AU - Aittomäki, Kristiina
AU - Blomqvist, Carl
AU - Chang-Claude, Jenny
AU - Rudolph, Anja
AU - Seibold, Petra
AU - Flesch-Janys, Dieter
AU - Wang, Xianshu
AU - kConFab Investigators
PY - 2014/4/1
Y1 - 2014/4/1
N2 - 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.
AB - 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.
KW - Breast Neoplasms
KW - Case-Control Studies
KW - Epistasis, Genetic
KW - Female
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Logistic Models
KW - Polymorphism, Single Nucleotide
U2 - 10.1093/hmg/ddt581
DO - 10.1093/hmg/ddt581
M3 - Journal article
C2 - 24242184
VL - 23
SP - 1934
EP - 1946
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 7
ER -