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Osteoarthritis Risk Linked to Novel Genetic Loci

NEW YORK (GenomeWeb) – A meta-analysis of samples from Iceland and the UK Biobank has uncovered novel loci linked to osteoarthritis.

Osteoarthritis affects more than 30 million adults in the US, especially those over the age of 70, according to the Centers for Disease Control and Prevention. Last year, researchers from Iceland tied variants in the COMP and CHADL genes to hip osteoarthritis risk, and earlier this year, a Wellcome Trust Sanger Institute-led team reported nine novel osteoarthritis loci, noting a correlation between osteoarthritis in the knees and BMI.

In a new study published today in Nature Genetics, Kari Stefansson from Decode Genetics, which is part of Amgen, and his colleagues conducted a meta-analysis drawing on both the Decode and UK Biobank datasets. Within this cohort of more than 600,000 individuals, they uncovered 23 associations at 22 loci, including 16 novel ones. One variant hinted at a role for the Hedgehog signaling pathway in disease, while other variants suggested a complex relationship between osteoarthritis risk and height.

"We find that a large fraction of the osteoarthritis risk variants associate with height, with the risk alleles associating with either increased or decreased height, suggesting that these associations disturb pathways that affect the growth and differentiation of bone and cartilage in ways that affect height both positively and negatively," the researchers wrote in their paper.

For this meta-analysis, the researchers combined data from the two biobanks on 17,151 hip osteoarthritis patients, 23,877 knee osteoarthritis patients, and more than 562,000 controls, focusing on the 11.6 million variants that could be imputed well in both datasets.

Using an additive model, they uncovered 23 independent association signals that reached genome-wide significance. This included 16 signals for hip and five for knee osteoarthritis. Two of these associations were rare missense variants, while the others were common and conferred small effects.

Meanwhile, using a recessive model, the researchers confirmed their previous report of a link between CHADL and hip osteoarthritis, and they found a link between the HFE gene and osteoarthritis, though only in the UK cohort.

One of the rare missense mutations the researchers identified fell in SMO, a gene in the Hedgehog signaling pathway. That pathway is a key part of embryonic development and the regulation of stem cell homeostasis, including osteogenesis, chrondrocyte differentiation regulation, and tissue regeneration later in life, the researchers noted. They traced the variant they uncovered in SMO to a cholesterol-binding site, suggesting that it has its effect by influencing the SMO-cholesterol complex. This, they said, appears to be the first study suggesting a link between the Hedgehog pathway and a common degenerative disease.

The researchers traced other signals to IL11, which encodes a cytokine involved in osteoclast differentiation and turnover, as well as to COL11A1, which encodes an extracellular matrix collagen expressed in cartilage. A number of other variants are within promoter or enhancer regions, which the researchers linked to genes like COL27A1, TNC, and WWP2 through Hi-C chromatin interaction mapping.

Previous work suggested links between height and BMI and osteoarthritis risk, and the researchers here noted a genetic association between BMI and knee and hip osteoarthritis. In addition, a number of the variants implicated in osteoarthritis are also associated with height in both the Decode and UK Biobank datasets. However, the researchers noted that some variants were associated with increased height, while others were linked to decreased height.

Overall, however, they found little genetic correlation between height and knee or hip osteoarthritis. The researchers said they suspected this was due to the effects of the different variants working in opposite directions and cancelling each other out. This indicates a complex relationship between height and osteoarthritis risk, they added.