NEW YORK – An international team has delved into common and rare variant contributors to osteoarthritis, identifying a subset of related genes that may serve as potential treatment targets.
For their study, outlined in a paper published in Nature on Wednesday, the researchers began by performing a genome-wide association study and GWAS meta-analysis involving 489,975 individuals with osteoarthritis and almost 1.5 million unaffected control individuals. The individuals were enrolled through dozens of prior studies, they explained, and included participants from several human population backgrounds.
More than 87 percent of those studies were of European descent. Almost 7.1 percent of the participants were of East Asian ancestry, while nearly 3.1 percent of participants had African American ancestry and 1.1 percent had ancestry from South Asia. Just over 0.9 percent of participants had Hispanic ancestry, and 0.53 percent had mixed ancestry.
"As no disease-modifying treatments exist for osteoarthritis, a better understanding of disease etiopathology is urgently needed," senior and corresponding author Eleftheria Zeggini, a translational genomics researcher with Helmholtz Zentrum Munich and the Technical University of Munich, and colleagues explained, noting that the "societal and public health burden of osteoarthritis is enormous and is accompanied by substantial multimorbidity and significant cost."
The team's analyses led to 962 osteoarthritis-related variants, including 513 variants not implicated in the condition in the past, while follow-up analyses that included single-cell multiomic, transcriptomic, proteomic, and epigenomic data generated on joint tissue samples highlighted some 700 high-confidence effector genes.
The follow-up analyses, which included published ATAC and RNA sequencing data spanning dozens of cell types profiled for a paper published in Nature in late 2024, suggested that osteoarthritis risk variants may be functionally enriched in cell types contributing to skeletal development.
The osteoarthritis risk variants and genes also appeared to be concentrated in pathways behind eight biological processes, ranging from retinoic acid signaling and extracellular matrix organization to circadian clock activity, the investigators explained.
"We discovered over 900 genetic associations, 500 of which have never been reported before, providing fresh insights into the genetic landscape of the disease," Zeggini said in an email, noting that "[t]argeted interventions regulating one or more of these eight processes could play a significant role in slowing or even halting disease progression."
Along with causal variant fine-mapping and analyses of risk allele carriage in the study participants, the team went on to look for overlap between apparent effector genes and potential treatment targets, for example, flagging 69 effector genes with protein products expected to be impacted by 473 approved drugs.
"This osteoarthritis GWAS meta-analysis is a substantial increase in size and power compared to previous studies," Zeggini said. "However, there is a clear need to continue efforts in identifying and including cohorts that better reflect diversity globally."
With that in mind, members of the team are interested in understanding osteoarthritis genetics through studies of still larger and more diverse cohorts, along with complementary functional research done in disease-relevant tissue types from individuals spanning diverse human populations.
"Going forward … the generation of functional genomics data from global populations across relevant disease tissues is highly warranted," the authors suggested. "The arising insights can spur clinical translation pathways to achieve an improvement in quality of life for the hundreds of millions of individuals affected by osteoarthritis currently left without anything but symptomatic treatment with modest effect."