LAUSR

BACKGROUND Frailty is strongly associated with cardiometabolic diseases in observational studies. However, whether the observed association reflects causality requires clarification. We performed a bidirectional Mendelian randomisation (MR) study to assess the causal relationship of frailty, measured by the frailty index (FI), with coronary artery disease (CAD), stroke and type 2 diabetes (T2D). METHODS We extracted summary genome-wide association statistics for the FI (N = 175,226), CAD (Ncase = 60,801, Ncontrol = 123,504), stroke (Ncase = 40,585, Ncontrol = 406,111) and T2D (Ncase = 55,005, Ncontrol = 400,308) among individuals of European ancestry. Independent genetic variants associated with each phenotype at the genome-wide significance level were taken as instruments. Two-sample MR analyses were primarily conducted using the inverse-variance-weighted method, followed by various sensitivity and validation analyses. RESULTS Genetically predicted higher FI was significantly associated with increased risk of CAD (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.17-1.96) and T2D (OR 1.80, 95% CI 1.31-2.47) and suggestively associated with higher risk of stroke (OR 1.36, 95% CI 1.01-1.84). In the reverse direction analysis, genetic liability to CAD (beta 0.037, 95% CI 0.019-0.055), stroke (beta 0.096, 95% CI 0.051-0.141) and T2D (beta 0.047, 95% CI 0.036-0.059) showed significant associations with increased FI. Results were stable across sensitivity and validation analyses. CONCLUSION Our study strengthened the evidence for a bidirectional causal association between frailty and cardiometabolic diseases. Further understanding of this association will be critical for the optimisation of care in older adults.