美国科罗拉多大学Andrew D. Grotzinger课题组取得一项新突破。他们发现了利用基因组结构方程模型揭示脆弱性的多变量遗传结构。相关论文于2025年8月4日发表在《自然—遗传学》杂志上。

在这里，课题组研究人员对30个脆弱缺陷之间的潜在遗传结构进行了多变量全基因组关联研究，确定了408个基因组风险位点。他们的模型包括所有缺陷中基因重叠的一般因素，以及六个新因素，这些因素在特定缺陷群体中索引共享的遗传信号。研究组展示了这六个因素的附加临床和病因学价值，包括预测外部数据集的脆弱性，强调与临床相关结果的不同遗传相关性，以及揭示与衰老相关的独特潜在生物学。课题组表明，细致入微的虚弱模型是理解其主题及其与健康状况恶化之间关系的关键。

研究人员表示，虚弱是一种多方面的临床状态，与加速衰老和不良健康结果有关。知情的虚弱病因学模型有望在老龄人口中产生广泛的健康改善。虚弱目前是用总分来衡量的，这模糊了只与虚弱的子成分相关的病因途径。

附：英文原文

Title: Uncovering the multivariate genetic architecture of frailty with genomic structural equation modeling

Author: Foote, Isabelle F., Flint, Jonny P., Frtjes, Anna E., Lawrence, Jeremy M., Mullin, Donncha S., Fisk, John D., Karakach, Tobias K., Rutenberg, Andrew, Martin, Nicholas G., Lupton, Michelle K., Llewellyn, David J., Ranson, Janice M., Cox, Simon R., Luciano, Michelle, Rockwood, Kenneth, Grotzinger, Andrew D.

Issue&Volume: 2025-08-04

Abstract: Frailty is a multifaceted clinical state associated with accelerated aging and adverse health outcomes. Informed etiological models of frailty hold promise for producing widespread health improvements across the aging population. Frailty is currently measured using aggregate scores, which obscure etiological pathways that are only relevant to subcomponents of frailty. Here we perform a multivariate genome-wide association study of the latent genetic architecture between 30 frailty deficits, which identifies 408 genomic risk loci. Our model includes a general factor of genetic overlap across all deficits, plus six new factors indexing a shared genetic signal across specific groups of deficits. We demonstrate the added clinical and etiological value of the six factors, including predicting frailty in external datasets, highlighting divergent genetic correlations with clinically relevant outcomes and uncovering unique underlying biology linked to aging. We show that nuanced models of frailty are key to understanding its causes and how it relates to worse health.

DOI: 10.1038/s41588-025-02269-0

Source: https://www.nature.com/articles/s41588-025-02269-0