Escape from X inactivation drives sex differences and female trait variation.

X chromosome inactivation (XCI) partially balances gene dosage between sexes, yet expression from the inactive X (Xi) is variable across genes. In this study, we investigate whether gene-level Xi expression predicts transcriptional and phenotypic consequences of X-linked variation. We find that Xi expression levels are a strong linear predictor of female-male expression differences, suggesting that other compensatory or regulatory mechanisms play a more minor role in sex differences in X-linked gene expression. Among females, we identify three traits-lymphocyte percentage, HbA1c, and schizophrenia-for which higher Xi expression correlates with the strength of evidence for dominance effects. We hypothesize that an underappreciated mechanism could generate dominance effects of X-linked variants on a trait-specifically when the variant influences skew in X inactivation. This work establishes Xi expression as essential for understanding sex differences and the female-specific genetic basis of disease.