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Genetics of osteoarthritis

Epidemiological studies have demonstrated a major genetic component to osteoarthritis (OA), with heritability estimates of over 50% for most joint sites. These studies have also highlighted differences in the degree of OA heritability between joint sites and between the sexes, implying a high level of heterogeneity.

We published a genome-wide scan in 1999. We had focused on families containing siblings with severe large-joint OA ascertained by joint-replacement surgery. Our data showed that OA genetic susceptibility did exhibit joint specificity and that this susceptibility had a greater role in female disease. During the past 5 years we have been investigating our linkage regions and we have so far identified FRZB (chromosome 2q32.1), COL9A1 (6q12-q13), BMP5 (6p12.1) and IL4R (16p12.1-p11.2) as encoding for OA susceptibility. Common variants at these genes affect either the structural properties of the protein (FRZB and IL4R) or the transcription of the gene (BMP5 and COL9A1). The variants are particularly relevant to the development of hip OA in females.

What is particularly interesting about our recent discoveries is that the proteins encoded for by IL4R, BMP5 and FRZB are involved in chondrocyte cell signalling and signal transduction pathways. It appears probable, therefore, that OA genetic risk for the hip is principally accounted for by aberrant cell signalling. This was not anticipated.

In this presentation I will focus on our latest genetic findings. I will also discuss the results from other studies. A number of OA genome-wide scans have been performed, some on large joints and others investigating hand disease. Many loci appear unique to one particular study, with only some loci being positive in multiple studies. The reasons for this will be discussed.

A concern often expressed at orthopaedic and rheumatology meetings is that genetic linkages and associations are not consistently reproduced. These are reasonable criticisms but it needs to be remembered that the genetic component of a complex trait such as OA will not be mediated by fully penetrant risk alleles. Instead, any one allele will contribute only a fraction of the overall risk and this allele will, by chance, have varying frequencies in different cohorts. It is unreasonable, therefore, to expect a linkage or an association in one cohort to be replicated in all cohorts.


Our research was funded by Research into Ageing, The Arthritis Research Campaign, The Nuffield Foundation and The Wellcome Trust.

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Loughlin, J., Ferreira, A., Dowling, B. et al. Genetics of osteoarthritis. Arthritis Res Ther 6 (Suppl 3), 2 (2004).

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  • Osteoarthritis
  • Risk Allele
  • Genetic Component
  • Heritability Estimate
  • Genetic Finding