GTEx studies reveal variation in gene expression among individuals and, to small degree, by sex

September 10, 2020

Seven new studies from Science and Science Advances present the third and final phase of the Genotype-Tissue Expression (GTEx) project, begun over a decade ago by scientists aiming to better understand the effects of genetic diversity in healthy individuals. The results, based on an increased number of tissues and individuals, reveal population-specific and sex-specific differences in gene expression that could help inform how gene variants impact aging and disease.

One question the GTEx project explored is how sex differences in gene expression - which are broadly shared across mammals - differ in males and females. In a study in this package by Meritxell Oliva et al., researchers report that more than one-third of genes show sex-biased expression in at least one tissue, and that the genes that show differences between sexes are enriched for multiple pathways, including in immune responses and cancer. The authors hypothesize that this may contribute to the underlying sex-specific dysregulation for some diseases. The work of Oliva and colleagues also shows how sex differences in gene expression vary based on cell type within a tissue, and across the genome and between individuals. In a Perspective, Melissa A. Wilson highlights the utility of their findings to the research community - a resource that could be used for future comparisons with diseased tissues, she says. She notes that future studies that include samples from males and females will need to account for the findings: "different sex ratios in cell type in cases versus controls may drive the gene expression signal more than the phenotype of interest." Four other GTEx studies in Science discuss the effects of gene regulation in human tissues (Francois Aguet et al.), identify functional rare genetic variation (Nicole Ferraro et al.), study predictors of telomere length (Kathryn Demanelis et al.), and report cell type-specific gene regulation (Sarah Kim-Hellmuth et al.). In a study in Science Advances using data from 360,000 UK Biobank individuals, Aine Duffy et al. investigated how tissue-specific differences could be used to inform drug side effects that often account for the failure of drug clinical trials. Their work highlights the need for tissue-specific drug delivery. In a second study in Science Advances, Milton Pividori et al. used a tool called PhenomeXcan to analyze 4,091 traits from 49 tissues, results they converted into a gene-based, searchable platform including 22,515 genes. By applying a method to help identify likely causal gene-trait associations, their analysis helps inform which complex genetic traits may be therapeutic targets, which has been difficult to do in past.

In her Perspective, Wilson highlights the valuable contribution of this body of work and of its transparently shared sample set, but she also identifies sampling biases that hinder investigation of interindividual variation. Just over two-thirds of the samples are from males, more than half of the samples come from people 50 years and older, and nearly 85% of samples collected came from white people of European descent. She concludes: "Given these limitations of the samples, it is even more surprising--and should be motivating to human geneticists--how much interindividual variation is observed in gene expression among the people included in the GTEx Consortium. This should be a call to projects to expand the representation of human variation in future studies."
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American Association for the Advancement of Science

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