Genome-Wide Study of the UK Biobank Highlights the Importance of the Homeobox-C Gene Cluster in Hip Fracture Risk.

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Hip fractures are among the most common major orthopaedic injuries globally, with one in three women and one in twelve men projected to sustain a hip fracture in their lifetime. Identifying genetic factors that contribute to hip fracture risk could improve risk stratification and inform prevention strategies. This study aims to identify genetic variants associated with hip fracture susceptibility through a genome-wide association study (GWAS). A GWAS was undertaken using the UK Biobank to identify risk loci for hip fractures. At the time of analysis, 2165 neck of femur fractures were identified among the 502507 participants. Thirteen SNPs in five putative haplotypes were identified as significantly associated with hip fracture using the stringent GWAS threshold of 5E-8. Two of these loci appear to affect HOXC8, either by influencing the 3' UTR (rs4142680[T]) or via the miRNA hsa-miR-196a (rs11614913[T]). These two SNPs were also found to be expression quantitative trait loci for homeobox-C cluster genes (HOXC6, HOXC9, and HOXC-AS1). Polymorphisms affecting homeobox-C cluster genes influence hip fracture risk in the general population. Future research should focus on validating these genetic associations and exploring optimal therapeutic interventions that could mitigate fracture risk in subpopulations carrying these polymorphisms.