Human Genetics of Osteoarthritis


Osteoarthritis (OA) has an important genetic contribution. Genetic studies in humans have identified molecules involved in signalling cascades that are important for the pathology of the joint components such as the bone morphogenetic protein growth differentiation factor 5. Genome‐wide association studies (GWAS) in Asians have uncovered a likely role for structural extracellular matrix components (double von Willebrand factor type A domain) and molecules involved in immune response, but these genes are not associated in Caucasian patients. In Caucasians, a number of OA susceptibility signals that have surpassed the genome‐wide significance level (p=5×10−8) have been identified. A locus on chr7q22 near the orphan receptor GPR22 was discovered from GWAS for knee OA. An analysis using a 1000‐genomes project‐based imputation identified a variant mapping near the MCF2L gene. GWA and functional studies revealed that the DOT1L gene on 19q13 is also associated with hip OA and cartilage thickness. Finally, a recent GWAS in the UK subjects revealed 8 more loci that increase risk for knee or hip OA.

Key Concepts:

  • Osteoarthritis has an important genetic contribution which has been explored in humans using linkage and genetic association studies.

  • Genome‐wide association studies and candidate gene studies have identified several consistent associations with large joint (hip and knee OA) and highlighted the complex genetics to this disease, with many genes contributing modestly to overall disease risk.

  • This genetic contribution to OA form has now been estimated to be in the order of 39–65%.

  • Some of the genes to come out from genetic association studies appear to relate to skeletal development mediated by bone morphogenetic proteins (GDF5) and Wnt signalling (DOT1L) genes as well as genes known to be related to cartilage metabolism (CHST11).

  • The functional role of many of the genes identified so far still remains to be elucidated.

Keywords: osteoarthritis; meta‐analysis; genome‐wide association study; post‐traumatic osteoarthritis

Figure 1.

Schematic diagram of the various mechanisms whereby genetic variation may contribute to risk of knee OA. External factors, such as age, gender, injury and lifestyle, along with genetic variation affect an individual's risk of developing incident OA and of OA progressing to a severe stage. These risk factors can also influence molecular, physiological and morphological features which, in turn, influence risk of both incidence and progression of OA. The genes identified to date with genome‐wide significance in either Asian or Caucasian populations to influence risk of knee OA are shown.

Figure 2.

Schematic diagram of the various mechanisms whereby genetic variation may contribute to risk of hip OA. External factors, such as age, gender, joint shape and occupation, along with genetic variation affect an individual's risk of developing incident OA and of OA progressing to a severe stage. The genes identified to date with genome‐wide significance in Asian and Caucasian populations to influence risk of hip OA are shown.



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Further Reading

Cornelis FM, Luyten FP and Lories RJ (2011) Functional effects of susceptibility genes in osteoarthritis. Discovery medicine 12(63): 129–139.

Gabay O (2012) Osteoarthritis: new perspectives. Journal of Spine 1(1): e101.

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van Meurs JB and Uitterlinden AG (2012) Osteoarthritis year 2012 in review: genetics and genomics. Osteoarthritis and Cartilage 20(12): 1470–1476.

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Valdes, Ana M(May 2013) Human Genetics of Osteoarthritis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024987]