Osteoarthritis (OA) is a heterogeneous disease of a highly polygenic nature; genome-wide association studies (GWASs) have so far uncovered 33 genetic variants that influence the risk for the disease. A meta-analysis of genotype data from the Icelandic population from deCODE genetics and the UK Biobank now adds a further 16 loci — 12 for hip and four for knee OA.

The study, published in Nature Genetics, combines data from >17,000 patients with hip OA and almost 24,000 with knee OA along with 562,000 individuals without OA as controls to analyse 11.6 million genetic variants in the largest GWAS for the disease.

Credit: Springer Nature Limited

Despite the previously reported (and here replicated) genetic correlation between hip and knee OA, none of the newly identified loci overlap between the two subtypes, lending support for the idea that hip and knee OA have different genetic aetiologies.

The authors highlight a rare missense variant in SMO (involved in osteogenesis and chondrocyte differentiation) that has an odds ratio of 2.84 for increasing risk of hip OA, as well as a low-frequency missense variant in IL11 (which encodes a stimulator of osteoclast differentiation) and two independent low-frequency variants in COL11A1 (which encodes a type XI collagen) as plausible candidates for modifying risk of hip OA. A majority of the identified common variants (variants with a minor allele frequency >5%) are in promoter and enhancer regions of relevant cell types (such as osteoblasts and chondrocytes), a finding that is consistent with other complex traits.

The authors also use Mendelian randomization to infer direct causal effects of anthropometric traits on the risk of OA and confirm a previously reported epidemiological correlation between BMI and both hip and knee OA

Although a number of the known 697 genetic variants for human height were also associated with OA, the effect direction was not consistent and no genetic correlation between height and OA could be concluded, a finding that is in contrast to epidemiological studies.

hip and knee OA have different genetic aetiologies

With a better understanding of the genetic basis of OA (and other diseases), polygenic risk scores could be used to predict risk and subtypes of the disease in the future.