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.
Strange
Amy
A
Capon
Francesca
F
Spencer
Chris C A
CC
Knight
Jo
J
Weale
Michael E
ME
Allen
Michael H
MH
Barton
Anne
A
Band
Gavin
G
Bellenguez
Céline
C
Bergboer
Judith G M
JG
Blackwell
Jenefer M
JM
Bramon
Elvira
E
Bumpstead
Suzannah J
SJ
Casas
Juan P
JP
Cork
Michael J
MJ
Corvin
Aiden
A
Deloukas
Panos
P
Dilthey
Alexander
A
Duncanson
Audrey
A
Edkins
Sarah
S
Estivill
Xavier
X
Fitzgerald
Oliver
O
Freeman
Colin
C
Giardina
Emiliano
E
Gray
Emma
E
Hofer
Angelika
A
Hüffmeier
Ulrike
U
Hunt
Sarah E
SE
Irvine
Alan D
AD
Jankowski
Janusz
J
Kirby
Brian
B
Langford
Cordelia
C
Lascorz
Jesús
J
Leman
Joyce
J
Leslie
Stephen
S
Mallbris
Lotus
L
Markus
Hugh S
HS
Mathew
Christopher G
CG
McLean
W H Irwin
WH
McManus
Ross
R
Mössner
Rotraut
R
Moutsianas
Loukas
L
Naluai
Asa T
AT
Nestle
Frank O
FO
Novelli
Giuseppe
G
Onoufriadis
Alexandros
A
Palmer
Colin N A
CN
Perricone
Carlo
C
Pirinen
Matti
M
Plomin
Robert
R
Potter
Simon C
SC
Pujol
Ramon M
RM
Rautanen
Anna
A
Riveira-Munoz
Eva
E
Ryan
Anthony W
AW
Salmhofer
Wolfgang
W
Samuelsson
Lena
L
Sawcer
Stephen J
SJ
Schalkwijk
Joost
J
Smith
Catherine H
CH
Ståhle
Mona
M
Su
Zhan
Z
Tazi-Ahnini
Rachid
R
Traupe
Heiko
H
Viswanathan
Ananth C
AC
Warren
Richard B
RB
Weger
Wolfgang
W
Wolk
Katarina
K
Wood
Nicholas
N
Worthington
Jane
J
Young
Helen S
HS
Zeeuwen
Patrick L J M
PL
Hayday
Adrian
A
Burden
A David
AD
Griffiths
Christopher E M
CE
Kere
Juha
J
Reis
André
A
McVean
Gilean
G
Evans
David M
DM
Brown
Matthew A
MA
Barker
Jonathan N
JN
Peltonen
Leena
L
Donnelly
Peter
P
Trembath
Richard C
RC
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