NEW YORK – An international research team led by investigators in Sweden has identified five genomic loci linked to hip fracture risk using a genome-wide association study, using Mendelian randomization to dig into related conditions or lifestyle factors.
As they reported in Cell Reports Medicine on Tuesday, researchers at the University of Gothenburg and other centers brought together data for 11,516 hip fracture cases and more than 723,800 unaffected control individuals from five biobanks from Northern Europe: the UK Biobank, Estonian Biobank, FinnGen, the Trøndelag Health Study (HUNT) in Norway, and Sweden's UFO.
"Hip fracture is the most severe type of fracture, associated with a high morbidity and mortality as well as high costs for society," senior and corresponding author Claes Ohlsson, an internal medicine and clinical nutrition researcher affiliated with the University of Gothenburg and Sahlgrenska University Hospital, and his colleagues wrote, noting that "hip fracture incidence increases exponentially by age."
The team's search led to five loci with significant hip fracture associations. These included four sites — in and around the REST, HOXC8, SALL1, and ETS2 genes — that showed significant ties to bone mineral density (BMD). A fifth risk locus was associated with falls but did not appear to impact BMD, consistent with a subsequent genetic correlation analysis that pointed to potential genetic overlap between falls and hip fracture.
With Mendelian randomization, meanwhile, the authors found that hip fracture risk strongly coincided with lower-than-usual femoral neck BMD. They suggested that the "substantial causal effect of decreased femoral neck BMD on hip fractures in both young and old subjects, and in both men and women supports the use of change in femoral neck BMD as a surrogate outcome for hip fractures in clinical trials."
Their analyses pointed to more moderate ties between hip fracture risk and Alzheimer's disease or to a history of smoking — correlations that appeared to stem from enhanced fall risk in individuals with Alzheimer's disease and in some smokers, along with related biological changes that may impact bone features or bone strength.
"The present study demonstrates that the genetic architecture of fractures is complex and at least partly differs by bone site, age, and gender and, for hip fractures, involves both BMD-related and non-BMD-related signals," the authors wrote.