Cortical Morphology and Susceptibility to Fall-Related Fractures: A Bidirectional Mendelian Randomization Study

Abstract

Aim

Injurious falls and low-energy fractures after a simple fall cause substantial morbidity in older adults; observational brain-structure associations are vulnerable to confounding and reverse causation. To test whether predicted regional cortical thickness or surface area causally influences falls and fractures after a simple fall, and to evaluate reverse causality.

Methods

Bidirectional two-sample Mendelian randomization used cortical morphology across 34 regions (> 51 000 Europeans). Outcomes were falls/tendency to fall and simple-fall fractures. Independent genome-wide significant instruments (p < 5 × 10⁻⁸) were clumped at r² = 0.001 within a 10 000 kb window, retained if SNP-level F statistics were > 10, and analyzed using inverse-variance weighted MR with sensitivity methods, pleiotropy/directionality checks, and Benjamini–Hochberg FDR correction. Estimated bone mineral density (eBMD) was explored as a potential mediator.

Results

After FDR correction and pleiotropy screening, larger caudal anterior cingulate surface area was associated with lower odds of fracture resulting from a simple fall (OR 0.95, 95% CI 0.92–0.98; pFDR = 0.0159), whereas larger insula surface area was related to higher odds of fracture resulting from a simple fall (OR 1.05, 95% CI 1.02–1.08; pFDR = 0.0037). Associations with the broader falls/tendency-to-fall phenotype were not robust. Reverse MR showed no evidence that falls or simple-fall fractures altered cortical traits, and exploratory eBMD analyses did not support mediation.

Conclusions

Genetically predicted surface area in the caudal anterior cingulate and insula was associated with susceptibility to fractures resulting from simple falls. These findings require replication and functional validation before specific neurobiological mechanisms or clinical applications can be inferred.