A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22.
OBJECTIVE
To identify novel genes involved in osteoarthritis (OA), by means of a genome-wide association study.


METHODS
We tested 500,510 single-nucleotide polymorphisms (SNPs) in 1,341 Dutch Caucasian OA cases and 3,496 Dutch Caucasian controls. SNPs associated with at least 2 OA phenotypes were analyzed in 14,938 OA cases and approximately 39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values <1 x 10(-7) considered genome-wide significant.


RESULTS
The C allele of rs3815148 on chromosome 7q22 (minor allele frequency 23%; intron 12 of the COG5 gene) was associated with a 1.14-fold increased risk (95% confidence interval 1.09-1.19) of knee and/or hand OA (P = 8 x 10(-8)) and also with a 30% increased risk of knee OA progression (95% confidence interval 1.03-1.64) (P = 0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (68 kb upstream of GPR22), which is associated with GPR22 expression levels in lymphoblast cell lines (P = 4 x 10(-12)). Immunohistochemistry experiments revealed that G protein-coupled receptor protein 22 (GPR22) was absent in normal mouse articular cartilage or synovium. However, GPR22-positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged with in vivo papain treatment or methylated bovine serum albumin treatment. GPR22-positive chondrocyte-like cells were also found in osteophytes in instability-induced OA.


CONCLUSIONS
Our findings identify a novel common variant on chromosome 7q22 that influences susceptibility to prevalence and progression of OA. Since the GPR22 gene encodes a G protein-coupled receptor, this is potentially an interesting therapeutic target.
Kerkhof
Hanneke J M
HJ
Erasmus Medical Centre, Rotterdam, The Netherlands.
Lories
Rik J
RJ
Meulenbelt
Ingrid
I
Jonsdottir
Ingileif
I
Valdes
Ana M
AM
Arp
Pascal
P
Ingvarsson
Thorvaldur
T
Jhamai
Mila
M
Jonsson
Helgi
H
Stolk
Lisette
L
Thorleifsson
Gudmar
G
Zhai
Guangju
G
Zhang
Feng
F
Zhu
Yanyan
Y
van der Breggen
Ruud
R
Carr
Andrew
A
Doherty
Michael
M
Doherty
Sally
S
Felson
David T
DT
Gonzalez
Antonio
A
Halldorsson
Bjarni V
BV
Hart
Deborah J
DJ
Hauksson
Valdimar B
VB
Hofman
Albert
A
Ioannidis
John P A
JP
Kloppenburg
Margreet
M
Lane
Nancy E
NE
Loughlin
John
J
Luyten
Frank P
FP
Nevitt
Michael C
MC
Parimi
Neeta
N
Pols
Huibert A P
HA
Rivadeneira
Fernando
F
Slagboom
Eline P
EP
Styrkársdóttir
Unnur
U
Tsezou
Aspasia
A
van de Putte
Tom
T
Zmuda
Joseph
J
Spector
Tim D
TD
Stefansson
Kari
K
Uitterlinden
André G
AG
van Meurs
Joyce B J
JB
D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D002460:Cell Line; D002897:Chromosomes, Human, Pair 7; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D009426:Netherlands; D015207:Osteoarthritis, Hip / Q000208:ethnology / Q000235:genetics*; D020370:Osteoarthritis, Knee / Q000208:ethnology / Q000235:genetics*; D010206:Papain / Q000494:pharmacology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D012307:Risk Factors; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D044465:White People / Q000235:genetics* / Q000706:statistics & numerical data
C531500:GPR22 protein, human; C531501:GPR22 protein, mouse; D043562:Receptors, G-Protein-Coupled; D012710:Serum Albumin, Bovine; D010206:Papain