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Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22.

ABSTRACT: OBJECTIVES:Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component. METHODS:A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets. RESULTS:With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p=9.2 × 10??), thereby confirming its role as a susceptibility locus for OA. CONCLUSION:The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, ?), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.

SUBMITTER: Evangelou E

PROVIDER: S-EPMC3615180 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22.

Evangelou Evangelos E Valdes Ana M AM Kerkhof Hanneke J M HJ Styrkarsdottir Unnur U Zhu Yanyan Y Meulenbelt Ingrid I Lories Rik J RJ Karassa Fotini B FB Tylzanowski Przemko P Bos Steffan D SD Akune Toru T Arden Nigel K NK Carr Andrew A Chapman Kay K Cupples L Adrienne LA Dai Jin J Deloukas Panos P Doherty Michael M Doherty Sally S Engstrom Gunnar G Gonzalez Antonio A Halldorsson Bjarni V BV Hammond Christina L CL Hart Deborah J DJ Helgadottir Hafdis H Hofman Albert A Ikegawa Shiro S Ingvarsson Thorvaldur T Jiang Qing Q Jonsson Helgi H Kaprio Jaakko J Kawaguchi Hiroshi H Kisand Kalle K Kloppenburg Margreet M Kujala Urho M UM Lohmander L Stefan LS Loughlin John J Luyten Frank P FP Mabuchi Akihiko A McCaskie Andrew A Nakajima Masahiro M Nilsson Peter M PM Nishida Nao N Ollier William E R WE Panoutsopoulou Kalliope K van de Putte Tom T Ralston Stuart H SH Rivadeneira Fernado F Saarela Janna J Schulte-Merker Stefan S Shi Dongquan D Slagboom P Eline PE Sudo Akihiro A Tamm Agu A Tamm Ann A Thorleifsson Gudmar G Thorsteinsdottir Unnur U Tsezou Aspasia A Wallis Gillian A GA Wilkinson J Mark JM Yoshimura Noriko N Zeggini Eleftheria E Zhai Guangju G Zhang Feng F Jonsdottir Ingileif I Uitterlinden Andre G AG Felson David T DT van Meurs Joyce B JB Stefansson Kari K Ioannidis John P A JP Spector Timothy D TD

Annals of the rheumatic diseases 20101110 2

<h4>Objectives</h4>Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component.<h4>Methods</h4>A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian popul ...[more]

PMID: 21068099

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Project description:BackgroundThe arcOGEN genome-wide association study reported the rs9350591 C/T single nucleotide polymorphism (SNP) as marking a region on chromosome 6q14.1 that is associated with hip osteoarthritis (OA) in Europeans, with an odds ratio (OR) of 1.18 and a p-value of 2.42 × 10(-9). rs9350591 is an intergenic SNP surrounded by seven genes within 1 Mb. Six of the genes are expressed in cartilage. We sought to characterise this signal to assess whether the association of rs9350591 with OA is mediated by modulating gene expression.MethodsTotal RNA was extracted from hip or knee cartilage of 161 OA patients and from hip cartilage of 29 non-OA patients who had undergone hip replacements as a result of neck-of-femur (NOF) fractures. We used quantitative PCR (qPCR) to measure overall gene expression, and pyrosequencing to assess allelic expression of the genes. A mesenchymal stem cell (MSC) differentiation model was used to assess gene expression during chondrogenesis.ResultsWe identified a significant decrease in the expression of SENP6 (p = 0.005) and MYO6 (p = 0.026) in OA hip cartilage relative to the non-OA hip control cartilage. However, we found no evidence for a correlation between gene expression and rs9350591 genotype for any of the six genes. In addition, we identified expression quantitative trait loci (eQTLs) operating on COL12A1, TMEM30A, SENP6 and MYO6, although these were not relevant to the OA associated signal. Finally, all genes were dynamically expressed during chondrogenesis.ConclusionsThe regulation of gene expression at this locus is complex, highlighted by the down-regulation of SENP6 and MYO6 in OA hip cartilage and by eQTLs operating on four of the genes at the locus. However, modulation of gene expression in the end-stage OA cartilage that we have investigated is not the mechanism by which this association signal is operating. As implied by the dynamic patterns of gene expression throughout chondrogenesis, the association signal marked by rs9350591 could instead be exerting its effects during joint development.

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Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22.

Publications

Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22.

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