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Updated: Sep 15, 2025

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特定途径的多基因评分大大增加了影响肝脏生物标志物的基因脂肪相互作用的发现

Kenneth E Westerman^1,2,3, Daniel I Chasman^2,4, W James Gauderman⁴

¹Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, United States.

medRxiv : the preprint server for health sciences

|July 15, 2025

概括

路径特定的多基因分数 (pPGS) 提供了一种强大的方法来发现肝脏生物标志物的基因环境相互作用. 这些得分提高了可解释性,并识别了超越标准多基因得分和全基因组相互作用研究的新机制特异信号.

科学领域:

遗传学遗传学是一个
生物标志物生物标志物
基因与环境的相互作用

背景情况:

多基因分数 (PGS) 用于检测复杂特征的基因环境 (GxE) 相互作用.
标准的PGS总结了遗传效应,但由于生物异质性,可以稀释特定途径的信号.
之前的研究发现了全基因组PGS与BMI对肝功能的相互作用,这表明了更多精细发现的潜力.

研究的目的:

利用路径特定的多基因分数 (pPGS) 来发现与脂肪和肝脏生物标志物相关的机制特定的GxE相互作用.
将PPGS的功率和解释性与标准PPGS和全基因组相互作用研究 (GWIS) 进行比较.

主要方法:

使用标准PGS,从KEGG途径获得的PPGS和GWIS测试了与三个肝脏生物标志物 (ALT,AST,GT) 的脂肪度 (BMI) 相互作用.
应用Bonferroni校正进行显著性测试 ( $p < 2.7 \times 10^{- 4}).$
评估了不同的途径集合 (KEGG,Hallmark,KEGG Medicus) 以评估它们对发现的影响.

主要成果:

确定了49个重要的pPGS×BMI对ALT的相互作用,其中80%无法通过GWIS位置解释.
在所有肝脏生物标志物中发现了BMI和83个独特的PPGS之间的相互作用.
证明了途径收集的选择显著影响GxE相互作用的发现.

结论:

pPGS促进了脂肪和肝脏生物标志物之间的GxE相互作用的强大和可解释的发现.
结果支持使用pPGS进行机制特定的GxE相互作用研究.
未来的研究应该探索更广泛的暴露和pPGS的结果.

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