Abstract
Frailty, depression, and gastroesophageal reflux disease (GERD) are prevalent and interrelated conditions, particularly among older adults. Although dietary factors are implicated in these conditions, their causal relationships remain uncertain. This study employs Mendelian randomization (MR) to investigate the bidirectional causal associations among dietary habits, frailty, depression, and GERD. We analyzed genome-wide association studies summary data for the frailty index and GERD from multiple datasets, along with dietary habit data from the UK Biobank. Depression data were derived from the FinnGen project, encompassing 500,000 Finnish individuals. Using 2-sample MR, we assessed causal relationships between frailty, depression, and GERD, as well as between dietary habits and frailty/depression. Primary analyses utilized inverse variance weighted methods, the primary analysis method was inverse variance weighting, supplemented by MR-Egger, simple mode, weighted median, and weighted mode analyses. Mediation and multivariable MR analyses were conducted to examine direct and indirect effects, with a focus on GERD's potential mediating role. We identified significant bidirectional causal relationships between frailty and GERD, frailty and depression, and depression and GERD. Frailty mediated 81.6% of the association between GERD and depression (P = .021), while GERD mediated 72.5% of the association between depression and frailty (P < .001). Additionally, GERD mediated the relationship between dietary habits and frailty. GERD plays a key mediating role in the interplay between frailty and depression. Dietary modifications, such as adjusting cereal and coffee intake, may help mitigate frailty.