A thorough understanding and identification of potential determinants leading to frailty are imperative for the development of targeted interventions aimed at its prevention or mitigation. We investigated the potential determinants of frailty in a cohort of 469,301 UK Biobank participants. The evaluation of frailty was performed using the Fried index, which encompasses measurements of handgrip strength, gait speed, levels of physical activity, unintentional weight loss, and self-reported exhaustion. EWAS including 276 factors were first conducted. Factors associated with frailty in EWAS were further combined to generate composite scores for different domains, and joint associations with frailty were evaluated in a multivariate logistic model. The potential impact on frailty when eliminating unfavorable profiles of risk domains was evaluated by PAFs. A total of 21,020 (4.4%) participants were considered frailty, 192,183 (41.0%) pre-frailty, and 256,098 (54.6%) robust. The largest EWAS identified 90 modifiable factors for frailty across ten domains, each of which independently increased the risk of frailty. Among these factors, 67 have the potential to negatively impact health, while 23 have been found to have a protective effect. When shifting all unfavorable profiles to intermediate and favorable ones, overall adjusted PAF for potentially modifiable frailty risk factors was 85.9%, which increases to 86.6% if all factors are transformed into favorable tertiles. Health and medical history, psychosocial factors, and physical activity were the most significant contributors, accounting for 11.9%, 10.4%, and 10.1% respectively. This study offers valuable insights for developing population-level strategies aimed at preventing frailty.

彻底了解和识别导致衰弱的潜在决定因素对于制定旨在预防或减轻衰弱的有针对性的干预措施至关重要。我们在 469,301 名英国生物样本库参与者的队列中调查了虚弱的潜在决定因素。使用 Fried 指数进行虚弱评估，该指数包括握力、步态速度、身体活动水平、无意性体重减轻和自我报告的疲惫的测量。首先进行了 EWAS 包括 276 个因素。进一步结合 EWAS 中与衰弱相关的因素以生成不同领域的综合评分，并在多变量 logistic 模型中评估与衰弱的联合关联。通过 PAF 评估消除风险域的不利概况时对衰弱的潜在影响。共有 21,020 名 （4.4%） 参与者被认为是虚弱的，192,183 名 （41.0%） 是衰弱前期的，256,098 名 （54.6%） 是健壮的。最大的 EWAS 在 10 个领域中确定了 90 个可改变的衰弱因素，每个因素都独立地增加了衰弱的风险。在这些因素中，67 个因素有可能对健康产生负面影响，而 23 个因素被发现具有保护作用。当将所有不利因素转移到中间和有利因素时，潜在可改变的衰弱风险因素的总体调整后 PAF 为 85.9%，如果所有因素都转化为有利的三分位数，则增加到 86.6%。健康和病史、社会心理因素和身体活动是最重要的贡献者，分别占 11.9% 、 10.4% 和 10.1%。这项研究为制定旨在预防衰弱的人群层面策略提供了有价值的见解。