Application of anin silicoapproach identifies a genetic locus withinITGB2,and itsinteractions withHSPG2 and FGF9,to be associated with anterior cruciateligament rupture risk

Abstract

We developed a Biomedical Knowledge Graph model that is phenotype and biological function-aware through integrating knowledge from multiple domains in a Neo4j, graph database. Allknown human genes were assessed through the model to identify potential new risk genes foranterior cruciate ligament (ACL) ruptures and Achilles tendinopathy (AT). Genes were prioritisedand explored in a case–control study comparing participants with ACL ruptures (ACL-R),including a sub-group with non-contact mechanism injuries (ACL-NON), to uninjured controlindividuals (CON). After genefiltering, 3376 genes, including 411 genes identified throughprevious whole exome sequencing, were found to be potentially linked to AT and ACL ruptures.Four variants were prioritised:HSPG2:rs2291826A/G,HSPG2:rs2291827G/A,ITGB2:rs2230528C/TandFGF9:rs2274296C/T. The rs2230528 CC genotype was over-represented in the CON groupcompared to ACL-R (p< 0.001) and ACL-NON (p< 0.001) and the TT genotype and T allele wereover-represented in the ACL-R group and ACL-NON compared to CON (p< 0.001) group. Severalsignificant differences in distributions were noted for the gene-gene interactions: (HSPG2:rs2291826, rs2291827 andITGB2:rs2230528) and (ITGB2:rs2230528 andFGF9:rs2297429).