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New Osteoarthritis Genetic Risk Loci Uncovered in Multi-Ancestry Analyses

NEW YORK – A team led by researchers at the University of Alabama at Birmingham has identified 10 new genetic loci linked to osteoarthritis, using multi-ancestry genome-wide association analyses and meta-analyses that included hundreds of thousands of individuals.

"We discovered both ancestry-specific osteoarthritis-associated variants as well as variants whose effects are shared across ancestry groups," first and corresponding author Merry-Lynn McDonald, a researcher affiliated with the Birmingham Veterans Affairs Health Care System and the University of Alabama at Birmingham, and her colleagues wrote in Nature Genetics on Monday.

Starting with array-based genotyping profiles for more than 163,000 Million Veteran Program (MVP) participants with European, African, Asian, or Hispanic ancestry, the researchers used a multi-ancestry meta-analysis to search for genetic variants that distinguished the 79,569 individuals with osteoarthritis from the 80,002 unaffected control individuals.

By bringing in data for UK Biobank participants with European, African, East Asian, and South Asian ancestry for further replication, meta-, and fixed effect "mega"-analyses, the team narrowed in on variants at 10 new and 17 known loci linked to the progressive joint disease within and across ancestry groups.

Still other significant associations turned up when the researchers performed ancestry-stratified analyses, including sites that encompassed expression quantitative trait loci active in skeletal muscle, brain, or other tissues. They also conducted  gene-set enrichment analyses that highlighted genes from pathways affecting everything from cartilage, bone, and connective tissue processes to skeletal system and biosynthesis pathways.

The team further explored the biological processes behind osteoarthritis, along with potential treatment targets, with a series of fine-mapping, transcriptome-wide imputation, and drug repurposing analyses.

"As no effective medical interventions for disease modification are available, osteoarthritis often progresses to its end stage, at which time only surgical options are available, usually in the form of total joint replacement," the authors explained. "A more thorough understanding of genetic influences of osteoarthritis is essential to develop targeted personalized approaches to treatment, ideally long before the end stage is reached."

Even so, the researchers pointed to the need for still larger and more diverse studies of osteoarthritis genetics in the future, cautioning that "[m]ulti-ancestry osteoarthritis-associated variants identified in the current report only begin to fill the void in terms of identifying the ancestry-independent osteoarthritis-associated variants needed to advance the development of polygenic risk scores."