Dissecting the genetic architecture of knee alignment reveals its contribution to osteoarthritis risk

ObjectivesTo investigate the biological and clinical relevance of knee alignment in osteoarthritis by integrating population-scale imaging, genome-wide association, and functional genetic analyses. MethodsFemorotibial angle was derived from dual-energy X-ray absorptiometry scans in UK Biobank using machine-learning methods. Associations with knee and hip osteoarthritis outcomes were assessed. A genome-wide association study of mean femorotibial angle was performed, followed by fine-mapping and pathway enrichment analyses. Mendelian randomization was used to explore potential causal relationships. ResultsVarus alignment was strongly and progressively associated with knee pain, knee osteoarthritis, and total knee replacement (HR 3.42 [95% CI 2.92, 4.02]), with no association observed for hip osteoarthritis. GWAS identified 20 independent loci associated with femorotibial angle, enriched for pathways related to skeletal development, cartilage biology, and endochondral ossification. Post-GWAS analyses demonstrated regulatory effects across fetal and adult joint tissues, supporting life course influences on alignment. Genetic correlation analyses showed shared architecture between femorotibial angle and knee osteoarthritis. Causal analyses suggested that genetic liability to osteoarthritis reduces femorotibial angle ({beta} -0.11 [-0.16, - 0.06]), while evidence for an overall causal effect of femorotibial angle on osteoarthritis risk was limited (OR 0.93 [0.79, 1.10]). ConclusionsKnee alignment and susceptibility to knee osteoarthritis are partially genetically determined. At the population level, these genetic determinants support a causal effect of osteoarthritis on knee alignment, whereas evidence for a causal effect of alignment on knee osteoarthritis was limited. Furthermore, this study identifies novel genetic loci linking knee alignment with pathways involved in skeletal development and cartilage biology relevant to osteoarthritis. Key messagesO_ST_ABSWhat is already known on this topic?C_ST_ABSO_LILower limb malalignment, particularly varus alignment, is associated with knee osteoarthritis. C_LIO_LIPrevious studies have been observational, limiting their ability to determine whether malalignment is a cause or consequence of osteoarthritis. C_LIO_LIGenetic influences on knee alignment have been recognized, but its underlying genetic architecture and relationship with osteoarthritis susceptibility remain poorly understood. C_LI What this study adds?O_LIThis study identifies 20 genetic loci associated with femorotibial angle, which demonstrate enrichment in molecular pathways responsible for bone and cartilage development and maintenance across the life course. C_LIO_LIInstrumental variables analyses using genetic data provides greater evidence that osteoarthritis has a causal influence on knee alignment than alignment has on osteoarthritis risk. C_LI How might this affect research, practice or policy?O_LIAt a population level, knee alignment should be considered a marker of disease severity and progression rather than a causal target for osteoarthritis prevention. C_LIO_LIThese findings support the use of alignment-modifying interventions, such as osteotomy and bracing, to slow progression in established osteoarthritis but not as a means of preventing disease onset in the general population. C_LIO_LINovel genetic pathways associated with varus deformity and osteoarthritis could guide future patient stratification and targeted treatment. C_LI