ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 14.14 | DOI: 10.1530/ey.18.14.14

Science 2020 Sep; 369(6509): eaba3066

By integrating sex-specific Genotype-Tissue Expression (GTEx) data with gene function and transcription factor binding annotations, these authors describe mechanisms contributing to sex differences in the human transcriptome.

Many complex human traits and diseases exhibit sex-specific characteristics. These sex differences have been variously attributed to hormones, sex chromosomes, genotype × sex effects, differences in behavior, and differences in environmental exposures. The GTEx project provides an opportunity to investigate the prevalence and genetic mechanisms of sex differences in the human transcriptome (RNA expression levels) by surveying many tissues that had not previously been characterized in this manner.

Using GTEx data, the authors generated a catalogue of sex differences in gene expression across 44 human tissues, analyzed 16 245 RNA-sequenced samples and genotypes of 838 adults. They discovered sex-specific effects on gene expression in 13 294 genes across all tissues. These are involved in drug and hormone response, embryonic development and tissue morphogenesis, fertilization, sexual reproduction and spermatogenesis, fat metabolism, cancer, and immune response. They suggest hormone-related transcription factor regulation and sex-differentiated distribution of epigenetic marks.

Sex differences in the autosomal regulation of gene expression were much less common (369 sex-biased eQTLs across all tissues) and were highly tissue-specific. They identified 58 gene-trait associations driven by genetic regulation of gene expression in a single sex. These include loci where sex-differentiated cell type abundances mediate genotype-phenotype associations, as well as loci where sex may play a more direct role in the underlying molecular mechanism of the association. For example, they identified a female-specific locus in the liver for the hexokinase HKDC1 that influences glucose metabolism in pregnant females, and subsequently impacts on birth weight of the offspring.

These are tissue-specific and tissue-shared drivers and mechanisms contributing to sex differences in the human transcriptome. Some are multiple sex-specific genetic effects on gene expression that colocalize with complex trait genetic associations.

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