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
- 1School of Clinical Medicine, University of Cambridge, Cambridge, UK
- 2Department of Surgery, University of Cambridge, Cambridge, UK
- 3Texas Tech University, Lubbock, Texas, USA
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: 19 studies met the inclusion criteria, predominantly small candidate-gene case–control designs. Importantly, these publications did not represent 19 independent cohorts. The largest prospective cohort included 790 women at risk at baseline, of whom 58 sustained an incident ACL injury and 732 remained without incident injury. COL5A1 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: COL5A1 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.
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BibTeX
@article{edmonds2026genetic,
title = {{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}},
author = {Chloe Jean Edmonds and Glenn J Browne and Wasim S Khan and Stephen M McDonnell},
journal = {BMJ Open Sport \& Exercise Medicine},
year = {2026},
month = nov,
doi = {10.1136/bmjsem-2026-003274},
url = {https://doi.org/10.1136/bmjsem-2026-003274},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - 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
AU - Chloe Jean Edmonds
AU - Glenn J Browne
AU - Wasim S Khan
AU - Stephen M McDonnell
PY - 2026
DA - 2026/11/02
JO - BMJ Open Sport & Exercise Medicine
DO - 10.1136/bmjsem-2026-003274
UR - https://doi.org/10.1136/bmjsem-2026-003274
AB - 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: 19 studies met the inclusion criteria, predominantly small candidate-gene case–control designs. Importantly, these publications did not represent 19 independent cohorts. The largest prospective cohort included 790 women at risk at baseline, of whom 58 sustained an incident ACL injury and 732 remained without incident injury. COL5A1 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: COL5A1 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.
SN - 2055-7647
ER -