1:1

blankpublication

Altogether, we established a benchmark dataset for aberrant gene underexpression prediction in 49 human tissues, addressing an unmet need in the area of high-impact variant effect prediction.

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.

Year of publication

2025

Source

Nature Communications

Link to cite

Acces to Link >

Author

Florian R. Hölzlwimmer, Jonas Lindner, Georgios Tsitsiridis, Nils Wagner, Francesco Paolo Casale, Vicente A. Yépez & Julien Gagneur

You might also be interested in

ERDERA interviews Prof. Radka Kaneva and Dr Petia Stratieva, two leading members of Bulgaria’s National Mirror Group (NMG), to explore how the country is working to align its rare disease ecosystem with European developments.
ERDERA joins the Wilhelm Foundation and the Gdansk Medical University and Clinical Centre to strengthen phenotype‑led diagnosis for people living with undiagnosed conditions
The two-day event will focus on translating research and policy initiatives into tangible benefits for Rare Disease patients through better prevention, diagnosis, and treatment.
A legislative own initiative file in the Parliament’s new public health committee sets out what an EU “rare disease action framework” could look like — and why it could change how Europe measures progress for patients.