Recalibrating differential gene expression by genetic dosage variance prioritizes functionally relevant genes

Tissue-specific recalibration. (A) Number of genes V^G_H is estimated for, both as the tissue agnostic mean and per tissue. (B) Per tissue correlation of tissue V^G_H estimates with the inferred V^G_I estimate, compared to correlation with the most highly correlated tissue. Horizontal lines are medians for all tissues. (C) Comparison in which tissue the V^G_HI of a gene is lowest. Compared to all other genes, known ASD genes are significantly more likely to have the lowest V^G_HI in one of the GTEx brain tissues. (D) Impact on GO term enrichment of using tissue-specific V^G_HI estimates (GTEx tissue Brain Frontal Cortex) compared to mean V^G_H for recalibration in a DE experiment by PsychENCODE comparing ASD patients and controls. These results indicate that high-coverage tissue-specific metrics of regulatory constraint from the new haplotype-based V^G estimates in GTEx increase the detection of biologically meaningful expression signatures in disease.