Identification of Novel Genetic Variants Associated with Knee Osteoarthritis Patients of South India using Whole Exome Sequencing

Knee Osteoarthritis is the most prevalent form of arthritis. It is a major contributor to disability worldwide. Its aetiology is multifactorial, involving genetic predisposition and environmental influences. Despite extensive investigation in European and East Asian populations, the genetic basis of kOA in South Indians remains largely unexplored. In this study, whole-exome sequencing was performed on clinically diagnosed kOA patients and healthy controls of South Indian origin to identify rare and novel variants contributing to disease risk. Sequencing data were systematically processed with candidate variants prioritised from known osteoarthritis-associated genes and further refined using nine in silico prediction tools. 7 rare, putatively pathogenic variants were identified in patients, notably in genes COL11A1, HTRA1, PLEC, RAPH1, SOX9, ATP7B and PXN . These genes converge in pathways central to extracellular matrix organization, collagen fibril assembly and cell junction organization, processes essential for cartilage integrity. Importantly, these variants are absent from existing clinical variant databases and genome-wide association datasets of European and East Asian ancestry, suggesting population-specific contributions to disease susceptibility. The findings underscore the importance of extending genomic studies to underrepresented groups, with implications for understanding population-specific genetic risk factors in osteoarthritis.