Genetic susceptibility to anterior cruciate ligament rupture in athletes: a genome-wide association case–control study

Anterior cruciate ligament (ACL) rupture is a common and severe injury in athletes, influenced by both environmental and intrinsic factors. Genetic susceptibility has been suggested, but robust associations remain limited. We performed an exploratory genome-wide association study (GWAS) to identify genetic variants associated with ACL rupture in a well-characterised athlete cohort. Case–control study. A total of 607 participants of European ancestry were included: 401 patients with ACL rupture (293 unilateral, 108 bilateral) and 206 screened athlete controls with no history of ACL injury. Genotyping was performed using the Illumina Global Screening Array, and association analyses were conducted using logistic regression under an additive model, adjusting for population stratification. Several loci showed suggestive associations ( p < 5 × 10⁻⁵), including variants in or near GALNT11, ITGAM, C10orf82, OR7E47P, HSPA12A, OPRD1, and NEK10. These genes are implicated in diverse biological processes, including inflammatory regulation, cellular stress responses, and ciliary function. No variants reached genome-wide significance ( p < 5 × 10⁻⁸). No genome-wide significant associations with ACL rupture were identified. However, several loci showed suggestive associations that highlight biological pathways related to inflammation, cellular stress responses, and ciliary function. These findings should be considered hypothesis-generating and require replication in larger independent cohorts before firm conclusions regarding their role in ACL injury susceptibility can be drawn.