Landscape of Gene Expression in the Human Body

A new data resource will help establish how differences in an individual’s genomic makeup can affect gene activity and contribute to disease.Nobi_Prizue/iStockphoto

Most genetic variations between people have little or no effect on health. The variants that have been linked to human health conditions often alter how genes are expressed—when and where they’re turned on and off. Scientists have only just begun to understand how these variations in different tissues of the body affect human biology and disease.

To help researchers gain deeper insights into how genetic variants affect gene activity and disease susceptibility, NIH launched an effort in 2010 to create a data resource and tissue bank. The Genotype-Tissue Expression (GTEx) project aims to collect tissue samples spanning 54 distinct body sites from 900 deceased donors, including samples from autopsy and organ donations and tissue transplant programs. The DNA and RNA from these samples are then analyzed for genetic variations and gene activity.

The GTEx project is supported by the NIH Common Fund and several NIH institutes. Initial findings from the 2-year pilot phase were published in a series of papers on May 8, 2015, in Science and other journals.

In the main Science paper, GTEx researchers analyzed gene activity in more than 1,600 samples of 43 different tissues types taken from 175 people. The scientists collected an average of 28 tissue samples per donor. Sophisticated software allowed them to compare genetic variants with the expression of different genes across the different tissues. This approach can reveal variants that affect gene activity, called expression quantitative trait loci (eQTLs). For the initial phase, they focused on the 9 most available tissues: fat, tibial artery, heart, lung, skeletal muscle, tibial nerve, skin (sun-exposed), thyroid, and blood.

The researchers found thousands of eQTLs specific to certain tissues and thousands that are shared. They were able to cluster genes into “modules” with coordinated expression patterns in different tissues. About 1 in 5 genes switched between modules in different people. The researchers found more than 2,000 variants correlated with module switching, which they dubbed module-switching QTLs (modQTLs). More than half of these variants hadn’t been found with previous methods.

The team demonstrated that eQTLs can boost the ability to detect associations with genetically complex disorders such as hypertension. They could also use the approach to pinpoint where in the body genetic variants might cause disease. For example, eQTLs with the greatest effects on 2 genes associated with blood pressure had their strongest effects in the tibial artery.

A companion study in Science examined patterns in gene activity across nearly 1,500 GTEx tissue samples. The researchers found that gene activity differed substantially more across tissues than across individuals. The activity of almost 2,000 genes varied with age, including genes in pathways related to neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. More than 750 genes showed differences in activity between men and women. This finding may lead to insights into why certain diseases affect men and women differently.

“GTEx was designed to sample as many tissues as possible from a large number of individuals in order to understand the causal effects of genes and variants, and which tissues contribute to predisposition to disease,” says Dr. Emmanouil Dermitzakis at the University of Geneva Faculty of Medicine, Switzerland, a coauthor of the main Science paper. “The number of tissues examined in GTEx provides an unprecedented depth of genomic variation. It gives us unique insights into how people differ in gene expression in tissues and organs.”

The papers describe several other types of analyses as well, including variants that alter the length of proteins and those that affect how genes are spliced (splicing QTLs, or sQTLs). As the GTEx project continues to collect and analyze tissue samples, this growing resource will help reveal how genetic variation affects human biology and suggest new approaches to disease.