A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22

Hanneke J M Kerkhof, Rik J. Lories, Ingrid Meulenbelt, Ingileif Jonsdottir, Ana M. Valdes, Pascal Arp, Thorvaldur Ingvarsson, Mila Jhamai, Helgi Jonsson, Lisette Stolk, Gudmar Thorleifsson, Guangju Zhai, Feng Zhang, Yanyan Zhu, Ruud Van Der Breggen, Andrew Carr, Michael Doherty, Sally Doherty, David T. Felson, Antonio GonzalezBjarni V. Halldorsson, Deborah J. Hart, Valdimar B. Hauksson, Albert Hofman, John P A Ioannidis, Margreet Kloppenburg, Nancy E Lane, John Loughlin, Frank P. Luyten, Michael C. Nevitt, Neeta Parimi, Huibert A P Pols, Fernando Rivadeneira, Eline P. Slagboom, Unnur Styrḱarsd́ottir, Aspasia Tsezou, Tom Van De Putte, Joseph Zmuda, Tim D. Spector, Kari Stefansson, Andŕe G. Uitterlinden, Joyce B J Van Meurs

Research output: Contribution to journalArticle

147 Citations (Scopus)

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 ∼39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values <1 x 10-7 considered genomewide 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. Conclusion. 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.

Original languageEnglish (US)
Pages (from-to)499-510
Number of pages12
JournalArthritis and Rheumatism
Volume62
Issue number2
DOIs
StatePublished - Feb 2010

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Genome-Wide Association Study
G-Protein-Coupled Receptors
Osteoarthritis
Chromosomes
Single Nucleotide Polymorphism
Proteins
Articular Cartilage
Chondrocytes
Meta-Analysis
Confidence Intervals
Osteophyte
Papain
Synovial Membrane
Knee Osteoarthritis
Linkage Disequilibrium
Knee Joint
Gene Frequency
Introns
Genes
Knee

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Kerkhof, H. J. M., Lories, R. J., Meulenbelt, I., Jonsdottir, I., Valdes, A. M., Arp, P., ... Van Meurs, J. B. J. (2010). A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22. Arthritis and Rheumatism, 62(2), 499-510. https://doi.org/10.1002/art.27184

A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22. / Kerkhof, Hanneke J M; Lories, Rik J.; Meulenbelt, Ingrid; Jonsdottir, Ingileif; Valdes, Ana M.; Arp, Pascal; Ingvarsson, Thorvaldur; Jhamai, Mila; Jonsson, Helgi; Stolk, Lisette; Thorleifsson, Gudmar; Zhai, Guangju; Zhang, Feng; Zhu, Yanyan; Van Der Breggen, Ruud; Carr, Andrew; Doherty, Michael; Doherty, Sally; Felson, David T.; Gonzalez, Antonio; Halldorsson, Bjarni V.; Hart, Deborah J.; Hauksson, Valdimar B.; Hofman, Albert; Ioannidis, John P A; Kloppenburg, Margreet; Lane, Nancy E; Loughlin, John; Luyten, Frank P.; Nevitt, Michael C.; Parimi, Neeta; Pols, Huibert A P; Rivadeneira, Fernando; Slagboom, Eline P.; Styrḱarsd́ottir, Unnur; Tsezou, Aspasia; Van De Putte, Tom; Zmuda, Joseph; Spector, Tim D.; Stefansson, Kari; Uitterlinden, Andŕe G.; Van Meurs, Joyce B J.

In: Arthritis and Rheumatism, Vol. 62, No. 2, 02.2010, p. 499-510.

Research output: Contribution to journalArticle

Kerkhof, HJM, Lories, RJ, Meulenbelt, I, Jonsdottir, I, Valdes, AM, Arp, P, Ingvarsson, T, Jhamai, M, Jonsson, H, Stolk, L, Thorleifsson, G, Zhai, G, Zhang, F, Zhu, Y, Van Der Breggen, R, Carr, A, Doherty, M, Doherty, S, Felson, DT, Gonzalez, A, Halldorsson, BV, Hart, DJ, Hauksson, VB, Hofman, A, Ioannidis, JPA, Kloppenburg, M, Lane, NE, Loughlin, J, Luyten, FP, Nevitt, MC, Parimi, N, Pols, HAP, Rivadeneira, F, Slagboom, EP, Styrḱarsd́ottir, U, Tsezou, A, Van De Putte, T, Zmuda, J, Spector, TD, Stefansson, K, Uitterlinden, AG & Van Meurs, JBJ 2010, 'A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22', Arthritis and Rheumatism, vol. 62, no. 2, pp. 499-510. https://doi.org/10.1002/art.27184
Kerkhof, Hanneke J M ; Lories, Rik J. ; Meulenbelt, Ingrid ; Jonsdottir, Ingileif ; Valdes, Ana M. ; Arp, Pascal ; Ingvarsson, Thorvaldur ; Jhamai, Mila ; Jonsson, Helgi ; Stolk, Lisette ; Thorleifsson, Gudmar ; Zhai, Guangju ; Zhang, Feng ; Zhu, Yanyan ; Van Der Breggen, Ruud ; Carr, Andrew ; Doherty, Michael ; Doherty, Sally ; Felson, David T. ; Gonzalez, Antonio ; Halldorsson, Bjarni V. ; Hart, Deborah J. ; Hauksson, Valdimar B. ; Hofman, Albert ; Ioannidis, John P A ; Kloppenburg, Margreet ; Lane, Nancy E ; Loughlin, John ; Luyten, Frank P. ; Nevitt, Michael C. ; Parimi, Neeta ; Pols, Huibert A P ; Rivadeneira, Fernando ; Slagboom, Eline P. ; Styrḱarsd́ottir, Unnur ; Tsezou, Aspasia ; Van De Putte, Tom ; Zmuda, Joseph ; Spector, Tim D. ; Stefansson, Kari ; Uitterlinden, Andŕe G. ; Van Meurs, Joyce B J. / A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22. In: Arthritis and Rheumatism. 2010 ; Vol. 62, No. 2. pp. 499-510.
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T1 - A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22

AU - Kerkhof, Hanneke J M

AU - Lories, Rik J.

AU - Meulenbelt, Ingrid

AU - Jonsdottir, Ingileif

AU - Valdes, Ana M.

AU - Arp, Pascal

AU - Ingvarsson, Thorvaldur

AU - Jhamai, Mila

AU - Jonsson, Helgi

AU - Stolk, Lisette

AU - Thorleifsson, Gudmar

AU - Zhai, Guangju

AU - Zhang, Feng

AU - Zhu, Yanyan

AU - Van Der Breggen, Ruud

AU - Carr, Andrew

AU - Doherty, Michael

AU - Doherty, Sally

AU - Felson, David T.

AU - Gonzalez, Antonio

AU - Halldorsson, Bjarni V.

AU - Hart, Deborah J.

AU - Hauksson, Valdimar B.

AU - Hofman, Albert

AU - Ioannidis, John P A

AU - Kloppenburg, Margreet

AU - Lane, Nancy E

AU - Loughlin, John

AU - Luyten, Frank P.

AU - Nevitt, Michael C.

AU - Parimi, Neeta

AU - Pols, Huibert A P

AU - Rivadeneira, Fernando

AU - Slagboom, Eline P.

AU - Styrḱarsd́ottir, Unnur

AU - Tsezou, Aspasia

AU - Van De Putte, Tom

AU - Zmuda, Joseph

AU - Spector, Tim D.

AU - Stefansson, Kari

AU - Uitterlinden, Andŕe G.

AU - Van Meurs, Joyce B J

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N2 - 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 ∼39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values <1 x 10-7 considered genomewide 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. Conclusion. 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.

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