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.
Rothman
Nathaniel
N
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
Garcia-Closas
Montserrat
M
Chatterjee
Nilanjan
N
Malats
Nuria
N
Wu
Xifeng
X
Figueroa
Jonine D
JD
Real
Francisco X
FX
Van Den Berg
David
D
Matullo
Giuseppe
G
Baris
Dalsu
D
Thun
Michael
M
Kiemeney
Lambertus A
LA
Vineis
Paolo
P
De Vivo
Immaculata
I
Albanes
Demetrius
D
Purdue
Mark P
MP
Rafnar
Thorunn
T
Hildebrandt
Michelle A T
MA
Kiltie
Anne E
AE
Cussenot
Olivier
O
Golka
Klaus
K
Kumar
Rajiv
R
Taylor
Jack A
JA
Mayordomo
Jose I
JI
Jacobs
Kevin B
KB
Kogevinas
Manolis
M
Hutchinson
Amy
A
Wang
Zhaoming
Z
Fu
Yi-Ping
YP
Prokunina-Olsson
Ludmila
L
Burdett
Laurie
L
Yeager
Meredith
M
Wheeler
William
W
Tardón
Adonina
A
Serra
Consol
C
Carrato
Alfredo
A
García-Closas
Reina
R
Lloreta
Josep
J
Johnson
Alison
A
Schwenn
Molly
M
Karagas
Margaret R
MR
Schned
Alan
A
Andriole
Gerald
G
Grubb
Robert
R
Black
Amanda
A
Jacobs
Eric J
EJ
Diver
W Ryan
WR
Gapstur
Susan M
SM
Weinstein
Stephanie J
SJ
Virtamo
Jarmo
J
Cortessis
Victoria K
VK
Gago-Dominguez
Manuela
M
Pike
Malcolm C
MC
Stern
Mariana C
MC
Yuan
Jian-Min
JM
Hunter
David J
DJ
McGrath
Monica
M
Dinney
Colin P
CP
Czerniak
Bogdan
B
Chen
Meng
M
Yang
Hushan
H
Vermeulen
Sita H
SH
Aben
Katja K
KK
Witjes
J Alfred
JA
Makkinje
Remco R
RR
Sulem
Patrick
P
Besenbacher
Soren
S
Stefansson
Kari
K
Riboli
Elio
E
Brennan
Paul
P
Panico
Salvatore
S
Navarro
Carmen
C
Allen
Naomi E
NE
Bueno-de-Mesquita
H Bas
HB
Trichopoulos
Dimitrios
D
Caporaso
Neil
N
Landi
Maria Teresa
MT
Canzian
Federico
F
Ljungberg
Borje
B
Tjonneland
Anne
A
Clavel-Chapelon
Francoise
F
Bishop
David T
DT
Teo
Mark T W
MT
Knowles
Margaret A
MA
Guarrera
Simonetta
S
Polidoro
Silvia
S
Ricceri
Fulvio
F
Sacerdote
Carlotta
C
Allione
Alessandra
A
Cancel-Tassin
Geraldine
G
Selinski
Silvia
S
Hengstler
Jan G
JG
Dietrich
Holger
H
Fletcher
Tony
T
Rudnai
Peter
P
Gurzau
Eugen
E
Koppova
Kvetoslava
K
Bolick
Sophia C E
SC
Godfrey
Ashley
A
Xu
Zongli
Z
Sanz-Velez
José I
JI
D García-Prats
María
M
Sanchez
Manuel
M
Valdivia
Gabriel
G
Porru
Stefano
S
Benhamou
Simone
S
Hoover
Robert N
RN
Fraumeni
Joseph F
JF
Silverman
Debra T
DT
Chanock
Stephen J
SJ
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