Genomewide Association Study of Fracture Nonunion Using Electronic Health Records

Nonunion is a clinically significant complication of fracture associated with worse outcomes, including increased pain, disability, and higher healthcare costs. The risk for nonunion is likely to be complex and multifactorial, and as such, the biology underlying such risk remains poorly understood. Genetic studies represent one approach to identify implicated biology for further investigation, but to date the lack of large cohorts for study has limited such efforts. We utilized the electronic health records of two large academic medical centers in Boston to identify individuals with fracture nonunion and control individuals with fracture but no evidence of nonunion. We conducted a genomewide association study among 1760 individuals of Northern European ancestry with upper or lower extremity fracture, including 131 with nonunion, to examine whether common variants were associated with nonunion in this cohort. In all, one locus in the Calcyon (CALY) gene exceeded a genomewide threshold for statistical significance (p = 1.95e-8), with eight additional loci associated with p < 5e-7. Previously reported candidate genes were not supported by this analysis. Electronic health records should facilitate identification of common genetic variations associated with adverse orthopedic outcomes. The loci we identified in this small cohort require replication and further study to characterize mechanism of action, but represent a starting point for the investigation of genetic liability for this costly outcome.