Aberrant expression prediction across human tissues

Abstract

AbstractDespite the frequent implication of aberrant gene expression in diseases, algorithms predicting aberrantly expressed genes of an individual are lacking. To address this need, we compiled an aberrant expression prediction benchmark covering 8.2 million rare variants from 633 individuals across 48 tissues. While not geared toward aberrant expression, the deleteriousness score CADD and the loss-of-function predictor LOFTEE showed mild predictive ability (1-1.5% average precision). Leveraging these and further variant annotations, we next trained AbExp, a model that yielded 10% 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 led 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.