Genetic susceptibility to anterior cruciate ligament rupture in females: a systematic review of female-stratified candidate-gene evidence and the absence of genome-wide studies
Year: 2026
Type: review
Study design: Systematic Review
Abstract: Objective: To systematically synthesise and critically appraise genetic association studies reporting female-stratified evidence for anterior cruciate ligament (ACL) rupture. Design: Systematic review. Data sources: Web of Science, Scopus, Ovid MEDLINE and the Cochrane Library were searched from database inception to 21 December 2025, which was the predefined search date for this review. Eligibility criteria for selecting studies: Human genetic association studies reporting female-stratified ACL rupture outcomes or extractable female-only data were included. Studies reporting combined-sex analyses without extractable female data were excluded. Due to predefined heterogeneity in phenotypes, populations and genetic models, findings were synthesised narratively. Results: rs12722 was the most frequently reported female-stratified candidate variant. Positive single-variant estimates principally concerned CC homozygotes under a recessive model and arose from South African samples with documented participant reuse. Separate allelic associations were also reported. Independence of this signal was limited by probable cohort overlap, heterogeneous genetic models and null prospective evidence. Evidence for other collagen, proteoglycan, inflammatory and extracellular matrix remodelling genes was inconsistent. No female-stratified genome-wide association studies were identified. Conclusions: rs12722 is the most frequently reported female-stratified candidate variant, but independent replication is not established. Positive recessive estimates concern CC homozygotes and should not be extended to heterozygotes. Small samples, participant reuse, heterogeneous genetic models and null prospective evidence limit certainty. Female-stratified associations do not establish sex-specific effects. Evidence derives predominantly from women of European ancestry, and generalisability to other ancestries remains unknown. Current findings do not support genetic screening for ACL rupture risk in female athletes; adequately powered, female-stratified genomic studies with rigorous phenotyping and independent replication across diverse ancestries are needed.
Institutions: University of Cambridge, Texas Tech University
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,839
OpenAlex ID: W7225091447