title: A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22.
abstract: 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.
authors.affiliation: Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Hanneke J M
authors.initials: HJ
authors.lastname: Kerkhof
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Lories
authors.forename: Ingrid
authors.initials: I
authors.lastname: Meulenbelt
authors.forename: Ingileif
authors.initials: I
authors.lastname: Jonsdottir
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
authors.forename: Pascal
authors.initials: P
authors.lastname: Arp
authors.forename: Thorvaldur
authors.initials: T
authors.lastname: Ingvarsson
authors.forename: Mila
authors.initials: M
authors.lastname: Jhamai
authors.forename: Helgi
authors.initials: H
authors.lastname: Jonsson
authors.forename: Lisette
authors.initials: L
authors.lastname: Stolk
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Guangju
authors.initials: G
authors.lastname: Zhai
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ruud
authors.initials: R
authors.lastname: van der Breggen
authors.forename: Andrew
authors.initials: A
authors.lastname: Carr
authors.forename: Michael
authors.initials: M
authors.lastname: Doherty
authors.forename: Sally
authors.initials: S
authors.lastname: Doherty
authors.forename: David T
authors.initials: DT
authors.lastname: Felson
authors.forename: Antonio
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Bjarni V
authors.initials: BV
authors.lastname: Halldorsson
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Hart
authors.forename: Valdimar B
authors.initials: VB
authors.lastname: Hauksson
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: John P A
authors.initials: JP
authors.lastname: Ioannidis
authors.forename: Margreet
authors.initials: M
authors.lastname: Kloppenburg
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
authors.forename: John
authors.initials: J
authors.lastname: Loughlin
authors.forename: Frank P
authors.initials: FP
authors.lastname: Luyten
authors.forename: Michael C
authors.initials: MC
authors.lastname: Nevitt
authors.forename: Neeta
authors.initials: N
authors.lastname: Parimi
authors.forename: Huibert A P
authors.initials: HA
authors.lastname: Pols
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Eline P
authors.initials: EP
authors.lastname: Slagboom
authors.forename: Unnur
authors.initials: U
authors.lastname: Styrkársdóttir
authors.forename: Aspasia
authors.initials: A
authors.lastname: Tsezou
authors.forename: Tom
authors.initials: T
authors.lastname: van de Putte
authors.forename: Joseph
authors.initials: J
authors.lastname: Zmuda
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
mesh_terms: 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
chemical_list: C531500:GPR22 protein, human; C531501:GPR22 protein, mouse; D043562:Receptors, G-Protein-Coupled; D012710:Serum Albumin, Bovine; D010206:Papain