A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.
We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
Nathaniel
N
Rothman
Montserrat
M
Garcia-Closas
Nilanjan
N
Chatterjee
Nuria
N
Malats
Xifeng
X
Wu
Jonine D
JD
Figueroa
Francisco X
FX
Real
David
D
Van Den Berg
Giuseppe
G
Matullo
Dalsu
D
Baris
Michael
M
Thun
Lambertus A
LA
Kiemeney
Paolo
P
Vineis
Immaculata
I
De Vivo
Demetrius
D
Albanes
Mark P
MP
Purdue
Thorunn
T
Rafnar
Michelle A T
MA
Hildebrandt
Anne E
AE
Kiltie
Olivier
O
Cussenot
Klaus
K
Golka
Rajiv
R
Kumar
Jack A
JA
Taylor
Jose I
JI
Mayordomo
Kevin B
KB
Jacobs
Manolis
M
Kogevinas
Amy
A
Hutchinson
Zhaoming
Z
Wang
Yi-Ping
YP
Fu
Ludmila
L
Prokunina-Olsson
Laurie
L
Burdett
Meredith
M
Yeager
William
W
Wheeler
Adonina
A
Tardón
Consol
C
Serra
Alfredo
A
Carrato
Reina
R
García-Closas
Josep
J
Lloreta
Alison
A
Johnson
Molly
M
Schwenn
Margaret R
MR
Karagas
Alan
A
Schned
Gerald
G
Andriole
Robert
R
Grubb
Amanda
A
Black
Eric J
EJ
Jacobs
W Ryan
WR
Diver
Susan M
SM
Gapstur
Stephanie J
SJ
Weinstein
Jarmo
J
Virtamo
Victoria K
VK
Cortessis
Manuela
M
Gago-Dominguez
Malcolm C
MC
Pike
Mariana C
MC
Stern
Jian-Min
JM
Yuan
David J
DJ
Hunter
Monica
M
McGrath
Colin P
CP
Dinney
Bogdan
B
Czerniak
Meng
M
Chen
Hushan
H
Yang
Sita H
SH
Vermeulen
Katja K
KK
Aben
J Alfred
JA
Witjes
Remco R
RR
Makkinje
Patrick
P
Sulem
Soren
S
Besenbacher
Kari
K
Stefansson
Elio
E
Riboli
Paul
P
Brennan
Salvatore
S
Panico
Carmen
C
Navarro
Naomi E
NE
Allen
H Bas
HB
Bueno-de-Mesquita
Dimitrios
D
Trichopoulos
Neil
N
Caporaso
Maria Teresa
MT
Landi
Federico
F
Canzian
Borje
B
Ljungberg
Anne
A
Tjonneland
Francoise
F
Clavel-Chapelon
David T
DT
Bishop
Mark T W
MT
Teo
Margaret A
MA
Knowles
Simonetta
S
Guarrera
Silvia
S
Polidoro
Fulvio
F
Ricceri
Carlotta
C
Sacerdote
Alessandra
A
Allione
Geraldine
G
Cancel-Tassin
Silvia
S
Selinski
Jan G
JG
Hengstler
Holger
H
Dietrich
Tony
T
Fletcher
Peter
P
Rudnai
Eugen
E
Gurzau
Kvetoslava
K
Koppova
Sophia C E
SC
Bolick
Ashley
A
Godfrey
Zongli
Z
Xu
José I
JI
Sanz-Velez
María
M
D García-Prats
Manuel
M
Sanchez
Gabriel
G
Valdivia
Stefano
S
Porru
Simone
S
Benhamou
Robert N
RN
Hoover
Joseph F
JF
Fraumeni
Debra T
DT
Silverman
Stephen J
SJ
Chanock
D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping / Q000379:methods; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015994:Incidence; D008297:Male; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D012727:Sex Characteristics; D012907:Smoking / Q000009:adverse effects; D013030:Spain / Q000453:epidemiology; D014481:United States / Q000453:epidemiology; D001749:Urinary Bladder Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human