NEW YORK – A team from the Erasmus Medical Center, German Research Center for Environmental Health, and elsewhere has unearthed 100 variants linked to osteoarthritis, including variants with ties to specific disease features and sex-specific risk variants.
"We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes," the authors reported in Cell on Thursday, adding that these findings "provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation."
At the moment, curative treatments remain elusive in osteoarthritis, which affects hundreds of millions of people around the world, corresponding author Eleftheria Zeggini, director of Helmholtz Zentrum München's Institute of Translational Genomics, elaborated in an email.
"An improved understanding of disease etiopathology and novel high-value drug targets are … urgently needed and eagerly anticipated," she said, adding that "we have gleaned multiple novel insights that substantially extend the field beyond what is currently known."
As part of the international Genetics of Osteoarthritis consortium, the researchers began with a genome-wide association study involving more than 177,500 individuals with osteoarthritis and nearly 649,200 unaffected controls enrolled through more than a dozen cohorts across nine populations. When they searched for variants that were over-represented in relation to 11 osteoarthritis phenotypes, they tracked down associated variants at 100 loci, including three loci with sex-specific effects and 52 loci that were not implicated in osteoarthritis in the past.
"We enhance our understanding of the genetic etiology of disease, shed biological insights, and provide a steppingstone for translating genetic associations into osteoarthritis drug development," the authors reported, "ultimately helping to catalyze an improvement in the lives of patients suffering from osteoarthritis."
Along with efforts to untangle genetic contributors to certain osteoarthritis symptoms such as pain or to symptoms turning up in specific parts of the body — from the hips or knees to hand or spine — the team turned to functional follow-up analyses that incorporated gene expression, methylation, expression quantitative trait locus, and protein quantitative trait locus, and phenotypic clues to focus in on causal or effector genes including potential drug targets.
"Our work provides a robust springboard for follow-up functional and clinical studies," the authors wrote. "We have demonstrated clear differences between distinct osteoarthritis patient populations, for example, based on disease severity, joint site affected, and sex."
In particular, the investigators pointed to the apparent importance of genes in pathways involved in skeletal development, neuronal development and function, joint degeneration, immunity, inflammation, and other processes.
Zeggini noted that the high-confidence effector genes they identified "offer evidence for the involvement of specific biological processes and of key molecular players within them."
While clinical trials are needed to explore possible treatment avenues, at least some of the genes unearthed in such analyses may serve as potential targets for existing treatments or compounds being developed.
"Our findings substantially strengthen the evidence for these potential therapeutics and provide novel drug repositioning opportunities," Zeggini said. "Our work offers a solid basis upon which to develop, or repurpose, such interventions for osteoarthritis."