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.