Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region.
Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 x 10(-5) were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17)), 16q22 (CDH1 and CDH3; P = 2.8 x 10(-8)) and 7q31 (LAMB1; P = 3.0 x 10(-8)). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.
Barrett
Jeffrey C
JC
Lee
James C
JC
Lees
Charles W
CW
Prescott
Natalie J
NJ
Anderson
Carl A
CA
Phillips
Anne
A
Wesley
Emma
E
Parnell
Kirstie
K
Zhang
Hu
H
Drummond
Hazel
H
Nimmo
Elaine R
ER
Massey
Dunecan
D
Blaszczyk
Kasia
K
Elliott
Timothy
T
Cotterill
Lynn
L
Dallal
Helen
H
Lobo
Alan J
AJ
Mowat
Craig
C
Sanderson
Jeremy D
JD
Jewell
Derek P
DP
Newman
William G
WG
Edwards
Cathryn
C
Ahmad
Tariq
T
Mansfield
John C
JC
Satsangi
Jack
J
Parkes
Miles
M
Mathew
Christopher G
CG
Donnelly
Peter
P
Peltonen
Leena
L
Blackwell
Jenefer M
JM
Bramon
Elvira
E
Brown
Matthew A
MA
Casas
Juan P
JP
Corvin
Aiden
A
Craddock
Nicholas
N
Deloukas
Panos
P
Duncanson
Audrey
A
Jankowski
Janusz
J
Markus
Hugh S
HS
Mathew
Christopher G
CG
McCarthy
Mark I
MI
Palmer
Colin N A
CN
Plomin
Robert
R
Rautanen
Anna
A
Sawcer
Stephen J
SJ
Samani
Nilesh
N
Trembath
Richard C
RC
Viswanathan
Anath C
AC
Wood
Nicholas
N
Spencer
Chris C A
CC
Barrett
Jeffrey C
JC
Bellenguez
Céline
C
Davison
Daniel
D
Freeman
Colin
C
Strange
Amy
A
Donnelly
Peter
P
Langford
Cordelia
C
Hunt
Sarah E
SE
Edkins
Sarah
S
Gwilliam
Rhian
R
Blackburn
Hannah
H
Bumpstead
Suzannah J
SJ
Dronov
Serge
S
Gillman
Matthew
M
Gray
Emma
E
Hammond
Naomi
N
Jayakumar
Alagurevathi
A
McCann
Owen T
OT
Liddle
Jennifer
J
Perez
Marc L
ML
Potter
Simon C
SC
Ravindrarajah
Radhi
R
Ricketts
Michelle
M
Waller
Matthew
M
Weston
Paul
P
Widaa
Sara
S
Whittaker
Pamela
P
Deloukas
Panos
P
Peltonen
Leena
L
Mathew
Christopher G
CG
Blackwell
Jenefer M
JM
Brown
Matthew A
MA
Corvin
Aiden
A
McCarthy
Mark I
MI
Spencer
Chris C A
CC
Attwood
Antony P
AP
Stephens
Jonathan
J
Sambrook
Jennifer
J
Ouwehand
Willem H
WH
McArdle
Wendy L
WL
Ring
Susan M
SM
Strachan
David P
DP
D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics*; D016022:Case-Control Studies; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D007797:Laminin / Q000235:genetics*
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C478221:LAMB1 protein, human; D007797:Laminin