The impact of sex on gene expression across human tissues

Abstract

Many complex human phenotypes exhibit sex-differentiated characteristics, however the underlying molecular mechanisms of these differences remain largely unknown. Here, we present an extensive catalog of both sex differences in gene expression and its genetic regulation across 44 human tissue sources surveyed by GTEx (v8 release). We demonstrate that sex strongly influences gene expression levels and cellular composition of tissue samples across the human body. The effect of sex on gene expression is widespread, with a total of 37% of all genes exhibiting sex-biased expression in at least one tissue. This suggests that many if not most biological processes, and thus complex traits and diseases, are impacted by sex effects on the transciptome. We expand the identification of cis-eQTLs with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation in a single sex, including novel associations not detected with sex-agnostic approaches. Altogether we provide the most comprehensive characterization of sex differences in the human transcriptome and its regulation to date.

Amplification is the Primary Mode of Gene-by-Sex Interaction in Complex Human Traits

“…Sex differences in polygenic effects on traits are clearly of high evolutionary [22][23][24][25][26] and translational [27][28][29][30][31] importance. Yet with the exception of testosterone levels [32][33][34][35] , the genetic basis of sexual dimorphism is not well-understood 31 .…”

“…GxSex may be a result of sex differences in environmental contexts or epistatic interaction with sex chromosomes. Sex differences in polygenic effects on traits are clearly of high evolutionary 22–26 and translational 27–31 importance. Yet with the exception of testosterone levels 32–35 , the genetic basis of sexual dimorphism is not well-understood 31 .…”

Sex-dependent transcriptional control of cardiac electrophysiology by histone acetylation modifiers based on the GTEx database

“…HDACs (11) HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11 SIRTs (7) SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7 o. These RNA-seq libraries were generated using non-strand specific, polyA-based Illumina TruSeq protocol and sequenced to a median depth of 78 million 76-bp paired-end reads.…”

“…Now, these resources are being leveraged to estimate safety risk for drugs and to predict the outcomes of clinical trials [4][5][6], in hopes to reduce cost, time for drug development and potential side effects. Such analyses using the GTEx data have brought awareness to tissue specificity [1], cell specificity [7] and the impact of sex on key molecular pathways and transcriptional control mechanisms [7][8][9][10]. For example, the GTEx dataset has been useful in identifying heart-specific genes implicated in pathologies, and in exploring cardiac tissue-specific relationships and regulators as well as transcriptome-wide differences between the ventricles and the atria [8] [9,[11][12][13][14][15][16].…”

“…Prior failed drugs and recent computational data stress the need for addressing diversity in responses – for example, a drug-response risk classifier trained on male data underpredicts arrhythmia risk in females[18]. Hormonal effects are now believed to only partially explain sex differences in these functional responses, as the GTEx data analysis has revealed that about 37% of all genes (majority of these autosomal) exhibit sex-differential gene expression in at least one tissue, including in the LV of the heart, where over 1300 genes have differential sex expression[7]. Importantly, among the most sex-differentially expressed genes are those involved in ion transport processes and response to drugs, including ion channels and CYP enzymes[6, 7, 19].…”