The genetics of falling susceptibility and identification of causal risk factors.

Falls represent a huge health and economic burden. Whilst many factors are associated with fall risk (e.g. obesity and physical inactivity) there is limited evidence for the causal role of these risk factors. Here, we used hospital and general practitioner records in UK Biobank, deriving a balance specific fall phenotype in 20,789 cases and 180,658 controls, performed a Genome Wide Association Study (GWAS) and used Mendelian Randomisation (MR) to test causal pathways. GWAS indicated a small but significant SNP-based heritability (4.4%), identifying one variant (rs429358) in APOE at genome-wide significance (P < 5e-8). MR provided evidence for a causal role of higher BMI on higher fall risk even in the absence of adverse metabolic consequences. Depression and neuroticism predicted higher risk of falling, whilst higher hand grip strength and physical activity were protective. Our findings suggest promoting lower BMI, higher physical activity as well as psychological health is likely to reduce falls.