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检测与可见神经网络的基因相互作用。

Detecting genetic interactions with visible neural networks.

作者信息

van Hilten Arno, Melograna Federico, Fan Bowen, Niessen Wiro, van Steen Kristel, Roshchupkin Gennady

机构信息

Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands.

BIO3 - Laboratory for Systems Medicine, Department of Human Genetics, KU Leuven, Leuven, Belgium.

出版信息

Commun Biol. 2025 Jun 5;8(1):874. doi: 10.1038/s42003-025-08157-x.

Abstract

Non-linear interactions among single nucleotide polymorphisms (SNPs), genes, and pathways play an important role in human diseases, but identifying these interactions is a challenging task. Neural networks are state-of-the-art predictors in many domains due to their ability to analyze big data and model complex patterns, including non-linear interactions. In genetics, visible neural networks are popular as they provide insight into the most important SNPs, genes, and pathways for prediction. Visible neural networks use prior knowledge (e.g., gene and pathway annotations) to define node connections in the network, making them sparse and interpretable. Currently, most of these networks provide measures for the importance of SNPs, genes, and pathways but do not provide information about interactions. In this paper, we explore different methods to detect non-linear interactions with visible neural networks. We adapt and speed up existing methods, create a comprehensive benchmark with simulated data from GAMETES and EpiGEN, and demonstrate that these methods can extract multiple types of interactions from trained neural networks. Finally, we apply these methods to a genome-wide case-control study of inflammatory bowel disease and find high consistency of the epistasis pairs candidates between interpretation methods. The follow-up association test on these candidates identifies seven significant epistasis pairs.

摘要

单核苷酸多态性(SNP)、基因和通路之间的非线性相互作用在人类疾病中起着重要作用,但识别这些相互作用是一项具有挑战性的任务。神经网络由于能够分析大数据并对复杂模式(包括非线性相互作用)进行建模,在许多领域都是最先进的预测工具。在遗传学中,可见神经网络很受欢迎,因为它们能深入了解预测中最重要的SNP、基因和通路。可见神经网络利用先验知识(如基因和通路注释)来定义网络中的节点连接,使其稀疏且可解释。目前,这些网络大多提供SNP、基因和通路重要性的度量,但不提供相互作用的信息。在本文中,我们探索了用可见神经网络检测非线性相互作用的不同方法。我们调整并加速了现有方法,用来自GAMETES和EpiGEN的模拟数据创建了一个综合基准,并证明这些方法可以从训练好的神经网络中提取多种类型的相互作用。最后,我们将这些方法应用于炎症性肠病的全基因组病例对照研究,发现不同解释方法之间上位性配对候选者具有高度一致性。对这些候选者进行的后续关联测试确定了七个显著的上位性配对。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c0c4/12141535/38029d2175be/42003_2025_8157_Fig1_HTML.jpg

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