Many pathophysiological mechanisms in human health and disease are dependent on sex. Systems biology approaches are successfully used to decipher human disease etiology, yet the effect of sex on gene network biology is mostly unknown. To address this, we used RNA-sequencing data of over 700 individuals spanning 24 tissues from the Genotype-Tissue Expression project to generate a whole-body gene activity map and quantified the sex differences per tissue. We found that of the 13,787 genes analyzed in 24 tissues, 20.1% of the gene activity is influenced by sex. For example, skeletal muscle was predominantly enriched with genes more active in males, whereas thyroid primarily contained genes more active in females. This was accompanied by consistent sex differences in pathway activity, including hypoxia, epithelial-to-mesenchymal transition, and inflammation over the human body. Furthermore, multi-organ analyses revealed consistent sex-dependent gene activity over numerous tissues which was accompanied by enrichment of transcription factor binding motifs in the promoters of these genes. Finally, we show that many sex-biased genes are known druggable targets. This emphasizes sex as a biological variable and the need to incorporate sex in systems biology studies. ### Competing Interest Statement The authors have declared no competing interest.
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