Genome-wide association study identifies novel breast cancer susceptibility loci.
Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
Easton
Douglas F
DF
CR-UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. d.easton@srl.cam.ac.uk
Pooley
Karen A
KA
Dunning
Alison M
AM
Pharoah
Paul D P
PD
Thompson
Deborah
D
Ballinger
Dennis G
DG
Struewing
Jeffery P
JP
Morrison
Jonathan
J
Field
Helen
H
Luben
Robert
R
Wareham
Nicholas
N
Ahmed
Shahana
S
Healey
Catherine S
CS
Bowman
Richard
R
Meyer
Kerstin B
KB
Haiman
Christopher A
CA
Kolonel
Laurence K
LK
Henderson
Brian E
BE
Le Marchand
Loic
L
Brennan
Paul
P
Sangrajrang
Suleeporn
S
Gaborieau
Valerie
V
Odefrey
Fabrice
F
Shen
Chen-Yang
CY
Wu
Pei-Ei
PE
Wang
Hui-Chun
HC
Eccles
Diana
D
Evans
D Gareth
DG
Peto
Julian
J
Fletcher
Olivia
O
Johnson
Nichola
N
Seal
Sheila
S
Stratton
Michael R
MR
Rahman
Nazneen
N
Chenevix-Trench
Georgia
G
Bojesen
Stig E
SE
Nordestgaard
Børge G
BG
Axelsson
Christen K
CK
Garcia-Closas
Montserrat
M
Brinton
Louise
L
Chanock
Stephen
S
Lissowska
Jolanta
J
Peplonska
Beata
B
Nevanlinna
Heli
H
Fagerholm
Rainer
R
Eerola
Hannaleena
H
Kang
Daehee
D
Yoo
Keun-Young
KY
Noh
Dong-Young
DY
Ahn
Sei-Hyun
SH
Hunter
David J
DJ
Hankinson
Susan E
SE
Cox
David G
DG
Hall
Per
P
Wedren
Sara
S
Liu
Jianjun
J
Low
Yen-Ling
YL
Bogdanova
Natalia
N
Schürmann
Peter
P
Dörk
Thilo
T
Tollenaar
Rob A E M
RA
Jacobi
Catharina E
CE
Devilee
Peter
P
Klijn
Jan G M
JG
Sigurdson
Alice J
AJ
Doody
Michele M
MM
Alexander
Bruce H
BH
Zhang
Jinghui
J
Cox
Angela
A
Brock
Ian W
IW
MacPherson
Gordon
G
Reed
Malcolm W R
MW
Couch
Fergus J
FJ
Goode
Ellen L
EL
Olson
Janet E
JE
Meijers-Heijboer
Hanne
H
van den Ouweland
Ans
A
Uitterlinden
André
A
Rivadeneira
Fernando
F
Milne
Roger L
RL
Ribas
Gloria
G
Gonzalez-Neira
Anna
A
Benitez
Javier
J
Hopper
John L
JL
McCredie
Margaret
M
Southey
Melissa
M
Giles
Graham G
GG
Schroen
Chris
C
Justenhoven
Christina
C
Brauch
Hiltrud
H
Hamann
Ute
U
Ko
Yon-Dschun
YD
Spurdle
Amanda B
AB
Beesley
Jonathan
J
Chen
Xiaoqing
X
Mannermaa
Arto
A
Kosma
Veli-Matti
VM
Kataja
Vesa
V
Hartikainen
Jaana
J
Day
Nicholas E
NE
Cox
David R
DR
Ponder
Bruce A J
BA
D000483:Alleles; D051017:Apoptosis Regulatory Proteins; D001210:Asia, Southeastern; D001315:Australia; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005060:Europe / Q000208:ethnology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D005838:Genotype; D006609:High Mobility Group Proteins; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D009656:North America; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D015534:Trans-Activators
D051017:Apoptosis Regulatory Proteins; D006609:High Mobility Group Proteins; C489183:LSP1 protein, human; D008840:Microfilament Proteins; D011980:Receptors, Progesterone; C521752:TOX3 protein, human; D015534:Trans-Activators; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human