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 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.
Human Cancer Genetics Programme and.
Roger L
RL
Milne
Jesús
J
Herranz
Kyriaki
K
Michailidou
Joe
J
Dennis
Jonathan P
JP
Tyrer
M Pilar
MP
Zamora
José Ignacio
JI
Arias-Perez
Anna
A
González-Neira
Guillermo
G
Pita
M Rosario
MR
Alonso
Qin
Q
Wang
Manjeet K
MK
Bolla
Kamila
K
Czene
Mikael
M
Eriksson
Keith
K
Humphreys
Hatef
H
Darabi
Jingmei
J
Li
Hoda
H
Anton-Culver
Susan L
SL
Neuhausen
Argyrios
A
Ziogas
Christina A
CA
Clarke
John L
JL
Hopper
Gillian S
GS
Dite
Carmel
C
Apicella
Melissa C
MC
Southey
Georgia
G
Chenevix-Trench
Anthony
A
Swerdlow
Alan
A
Ashworth
Nicholas
N
Orr
Minouk
M
Schoemaker
Anna
A
Jakubowska
Jan
J
Lubinski
Katarzyna
K
Jaworska-Bieniek
Katarzyna
K
Durda
Irene L
IL
Andrulis
Julia A
JA
Knight
Gord
G
Glendon
Anna Marie
AM
Mulligan
Stig E
SE
Bojesen
Børge G
BG
Nordestgaard
Henrik
H
Flyger
Heli
H
Nevanlinna
Taru A
TA
Muranen
Kristiina
K
Aittomäki
Carl
C
Blomqvist
Jenny
J
Chang-Claude
Anja
A
Rudolph
Petra
P
Seibold
Dieter
D
Flesch-Janys
Xianshu
X
Wang
Janet E
JE
Olson
Celine
C
Vachon
Kristen
K
Purrington
Robert
R
Winqvist
Katri
K
Pylkäs
Arja
A
Jukkola-Vuorinen
Mervi
M
Grip
Alison M
AM
Dunning
Mitul
M
Shah
Pascal
P
Guénel
Thérèse
T
Truong
Marie
M
Sanchez
Claire
C
Mulot
Hermann
H
Brenner
Aida Karina
AK
Dieffenbach
Volker
V
Arndt
Christa
C
Stegmaier
Annika
A
Lindblom
Sara
S
Margolin
Maartje J
MJ
Hooning
Antoinette
A
Hollestelle
J Margriet
JM
Collée
Agnes
A
Jager
Angela
A
Cox
Ian W
IW
Brock
Malcolm W R
MW
Reed
Peter
P
Devilee
Robert A E M
RA
Tollenaar
Caroline
C
Seynaeve
Christopher A
CA
Haiman
Brian E
BE
Henderson
Fredrick
F
Schumacher
Loic
L
Le Marchand
Jacques
J
Simard
Martine
M
Dumont
Penny
P
Soucy
Thilo
T
Dörk
Natalia V
NV
Bogdanova
Ute
U
Hamann
Asta
A
Försti
Thomas
T
Rüdiger
Hans-Ulrich
HU
Ulmer
Peter A
PA
Fasching
Lothar
L
Häberle
Arif B
AB
Ekici
Matthias W
MW
Beckmann
Olivia
O
Fletcher
Nichola
N
Johnson
Isabel
I
dos Santos Silva
Julian
J
Peto
Paolo
P
Radice
Paolo
P
Peterlongo
Bernard
B
Peissel
Paolo
P
Mariani
Graham G
GG
Giles
Gianluca
G
Severi
Laura
L
Baglietto
Elinor
E
Sawyer
Ian
I
Tomlinson
Michael
M
Kerin
Nicola
N
Miller
Federik
F
Marme
Barbara
B
Burwinkel
Arto
A
Mannermaa
Vesa
V
Kataja
Veli-Matti
VM
Kosma
Jaana M
JM
Hartikainen
Diether
D
Lambrechts
Betul T
BT
Yesilyurt
Giuseppe
G
Floris
Karin
K
Leunen
Grethe Grenaker
GG
Alnæs
Vessela
V
Kristensen
Anne-Lise
AL
Børresen-Dale
Montserrat
M
García-Closas
Stephen J
SJ
Chanock
Jolanta
J
Lissowska
Jonine D
JD
Figueroa
Marjanka K
MK
Schmidt
Annegien
A
Broeks
Senno
S
Verhoef
Emiel J
EJ
Rutgers
Hiltrud
H
Brauch
Thomas
T
Brüning
Yon-Dschun
YD
Ko
Fergus J
FJ
Couch
Amanda E
AE
Toland
Drakoulis
D
Yannoukakos
Paul D P
PD
Pharoah
Per
P
Hall
Javier
J
Benítez
Núria
N
Malats
Douglas F
DF
Easton
D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016015:Logistic Models; D020641:Polymorphism, Single Nucleotide