Abstract
Background:
Anterior cruciate ligament (ACL) injuries are one of the most common pediatric knee injuries requiring surgery. Evolutionary genetic signatures in human populations enable the genome-wide association study (GWAS) approach to identify associations between genetic variants and traits like ACL injury risk. Understanding the underlying genetic factors that contribute to ACL injury risk may enable development of targeted prevention and treatment strategies. This study aimed to illuminate genes over-represented in both a European and African cohort with a history of ACL injury.
Hypothesis:
We hypothesized that single nucleotide polymorphisms (SNPs) can be used to create a preliminary polygenic risk score (PRS) in European and African cohorts with a history of ACL injury.
Methods:
We conducted a GWAS in two independent cohorts, one with African ancestry and one with European ancestry. The African cohort included 108 cases (72 males, 36 females) and 1080 controls without ACL injury (720 males, 360 females). The European cohort included 232 cases (114 males, 118 females) and 2320 controls (1140 males, 1180 females). Cases and controls were unrelated (kinship coefficient < 0.0442). Genotyping was done using Illumina Genotyping BeadChips with at least 550,000 SNPs genotyped. Genome-wide imputation was performed with the TOPMed Imputation Server and Reference Panel. To score the subjects for their genetic risk of ACL injury, index SNPs were identified with P<1E-04 and r2 <0.1 in each 250kb distance.
Results:
2789 SNPs had P<1E-04 in the African cohort, and 1801 SNPs had P<1E-04 in the European cohort (Figure 1). 2053 genes mapped to these loci. Three genes, GMNN, RREB1, and TBC1D7, related to abnormal patella morphology were highlighted by over-representation analysis in both cohorts. Using SNPs identified in the European population, we observed significantly lower PRS in Europeans than in African subjects (Table 1).
Conclusion:
Over-representation of the genes GMNN, RREB1, and TBC1D7 in a population with a history of ACL rupture has not previously been reported in either an African or European cohort, making this study the first to indicate that GMNN, RREB1, and TBC1D7 may potentially be key genes associated with risk of ACL injury. Further, this study represents the largest of its kind to evaluate potential genetic associations with ACL injury risk in an African cohort. Additionally, the lower PRS for European subjects suggests that genetic variants contributing to ACL injury may have been subject to negative selection in the European population.
