Genetic risk scores are related to bone microarchitecture in US Army basic training.

Trainees in US Army basic combat training (BCT) frequently experience vitamin D deficiency and bone stress injuries. It remains unclear how genetic variation influences these outcomes, either through direct effects on skeletal adaptations to training or by increasing susceptibility to vitamin D insufficiency, which in turn affects skeletal adaptations and injury risk. This study investigated whether single-nucleotide polymorphisms (SNPs) or genetic risk scores (GRS) previously related to vitamin D and bone health were associated with tibial bone microarchitecture during BCT. A cohort of 2,550 healthy young adults (36% female) underwent high-resolution peripheral quantitative computed tomography scans at the distal tibia before BCT and, in a subset (n = 1,514), again after BCT. The following GRS or SNPs were evaluated: vitamin D receptor, vitamin D binding protein, 25-hydroxy-vitamin D (25-OHD)-GRS, adult-GRS, fracture-GRS, pediatric-GRS, Wingless/Int-1 (WNT)-GRS, RANK-RANKL-OPG-GRS (RANK-GRS), and mesenchymal stem cell differentiation GRS (Mes-GRS). Multivariable linear regression models were adjusted for age, sex, body mass index, and 25-OHD concentration. Following correction for multiple testing, 47 significant associations emerged. The adult-GRS was negatively associated with volumetric bone mineral density (vBMD), trabecular vBMD, and bone volume fraction in White non-Hispanic, Hispanic trainees, and Other Races Combined. The fracture-GRS was associated with trabecular and cortical microarchitecture across three groups/ethnicities, whereas the pediatric-GRS primarily showed associations in White non-Hispanic individuals. RANK-GRS correlated with trabecular microstructure in White non-Hispanic and Other Races Combined, and WNT-GRS was associated with cortical volumetric BMD in White non-Hispanics. No associations were observed between vitamin D SNPs or GRS and changes in bone during BCT. These findings suggest that GRS previously related to bone density and remodeling pathways are associated with bone microarchitecture in young adults, whereas vitamin D-related GRS were not associated with tibial microarchitecture during BCT.NEW & NOTEWORTHY In 2,550 US Army trainees undergoing basic combat training, genetic risk scores were associated with tibial volumetric BMD and microarchitecture measured by HR-pQCT. These effects persisted in skeletally mature young adults under intense mechanical loading and across ancestry groups. In contrast, vitamin D-related genetic variants were not associated with skeletal traits or adaptation. Large-scale validation in this well-characterized cohort strengthens evidence linking established bone loci to microarchitectural phenotypes.