A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10⁻⁸ and two loci with a combined P < 5 × 10⁻⁷). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻⁶). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.
Wellcome Trust Centre for Human Genetics, Oxford, UK.
Amy
A
Strange
Francesca
F
Capon
Chris C A
CC
Spencer
Jo
J
Knight
Michael E
ME
Weale
Michael H
MH
Allen
Anne
A
Barton
Gavin
G
Band
Céline
C
Bellenguez
Judith G M
JG
Bergboer
Jenefer M
JM
Blackwell
Elvira
E
Bramon
Suzannah J
SJ
Bumpstead
Juan P
JP
Casas
Michael J
MJ
Cork
Aiden
A
Corvin
Panos
P
Deloukas
Alexander
A
Dilthey
Audrey
A
Duncanson
Sarah
S
Edkins
Xavier
X
Estivill
Oliver
O
Fitzgerald
Colin
C
Freeman
Emiliano
E
Giardina
Emma
E
Gray
Angelika
A
Hofer
Ulrike
U
Hüffmeier
Sarah E
SE
Hunt
Alan D
AD
Irvine
Janusz
J
Jankowski
Brian
B
Kirby
Cordelia
C
Langford
Jesús
J
Lascorz
Joyce
J
Leman
Stephen
S
Leslie
Lotus
L
Mallbris
Hugh S
HS
Markus
Christopher G
CG
Mathew
W H Irwin
WH
McLean
Ross
R
McManus
Rotraut
R
Mössner
Loukas
L
Moutsianas
Asa T
AT
Naluai
Frank O
FO
Nestle
Giuseppe
G
Novelli
Alexandros
A
Onoufriadis
Colin N A
CN
Palmer
Carlo
C
Perricone
Matti
M
Pirinen
Robert
R
Plomin
Simon C
SC
Potter
Ramon M
RM
Pujol
Anna
A
Rautanen
Eva
E
Riveira-Munoz
Anthony W
AW
Ryan
Wolfgang
W
Salmhofer
Lena
L
Samuelsson
Stephen J
SJ
Sawcer
Joost
J
Schalkwijk
Catherine H
CH
Smith
Mona
M
Ståhle
Zhan
Z
Su
Rachid
R
Tazi-Ahnini
Heiko
H
Traupe
Ananth C
AC
Viswanathan
Richard B
RB
Warren
Wolfgang
W
Weger
Katarina
K
Wolk
Nicholas
N
Wood
Jane
J
Worthington
Helen S
HS
Young
Patrick L J M
PL
Zeeuwen
Adrian
A
Hayday
A David
AD
Burden
Christopher E M
CE
Griffiths
Juha
J
Kere
André
A
Reis
Gilean
G
McVean
David M
DM
Evans
Matthew A
MA
Brown
Jonathan N
JN
Barker
Leena
L
Peltonen
Peter
P
Donnelly
Richard C
RC
Trembath
D000626:Aminopeptidases / Q000235:genetics*; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D005060:Europe; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D015236:HLA-C Antigens / Q000235:genetics*; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide; D011565:Psoriasis / Q000235:genetics*; D012016:Reference Values; D018570:Risk Assessment
D015236:HLA-C Antigens; D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human