Aberrant gene expression prediction across human tissues

Florian R. Hölzlwimmer, Jonas Lindner, Georgios Tsitsiridis, Nils Wagner, Francesco Paolo Casale, Vicente A. Yépez and Julien Gagneur ()
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Florian R. Hölzlwimmer: Technical University of Munich
Jonas Lindner: Technical University of Munich
Georgios Tsitsiridis: Technical University of Munich
Nils Wagner: Technical University of Munich
Francesco Paolo Casale: Technical University of Munich
Vicente A. Yépez: Technical University of Munich
Julien Gagneur: Technical University of Munich

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Despite the frequent implication of aberrant gene expression in diseases, algorithms predicting aberrantly expressed genes of an individual are lacking. To address this need, we compile an aberrant expression prediction benchmark covering 8.2 million rare variants from 633 individuals across 49 tissues. While not geared toward aberrant expression, the deleteriousness score CADD and the loss-of-function predictor LOFTEE show mild predictive ability (1–1.6% average precision). Leveraging these and further variant annotations, we next train AbExp, a model that yields 12% average precision by combining in a tissue-specific fashion expression variability with variant effects on isoforms and on aberrant splicing. Integrating expression measurements from clinically accessible tissues leads to another two-fold improvement. Furthermore, we show on UK Biobank blood traits that performing rare variant association testing using the continuous and tissue-specific AbExp variant scores instead of LOFTEE variant burden increases gene discovery sensitivity and enables improved phenotype predictions.

Date: 2025
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DOI: 10.1038/s41467-025-58210-w

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