Program Highlights

GTEx Creates a Reference Data Set to Study Genetic Changes and Gene Expression

Research studies have identified links between many genetic variants (a change in DNA sequence) and common diseases (e.g. cancer, diabetes, hypertension, Alzheimer's disease). We are now aware that genetic variants can regulate genes being turned on or off, which may contribute to complex diseases. However, which genes are turned on or off varies a lot in healthy people depending on which tissue type (e.g. heart, lung, brain, etc.) is being examined, and this makes it even harder to link a specific genetic variant to disease. The NIH Common Fund’s Genotype-Tissue Expression (GTEx) project has developed a reference data set for studying genetic variants and gene activity in multiple healthy tissues. This catalogue has stimulated research that will enrich our understanding of how differences in our DNA sequence contribute to health and disease, and make us different from everyone else. GTEx researchers, Eric Gamazon, Nancy Cox, and Hae Kyung Im used the GTEx reference data set to design a statistical method called PrediXcan that estimates how much of gene activity (whether a gene is turned on or off) is due to differences in DNA sequence.1 PrediXcan then links this estimate with observable traits as a way to identify genes associated with disease. The authors used this method to identify specific genes associated with five diseases: bipolar disorder, coronary artery disease, Crohn's disease, rheumatoid arthritis and type 1 diabetes. In another study, researchers used GTEx data to mathematically measure gene activity changes associated with a given genetic variant. This is a significant approach for investigating how genetic variants affect cellular processes.2 All GTEx data are publicly available at the GTEx Portal, which gives researchers everywhere access to the reference data set. Access to the data set will create new opportunities to study links between genetics and disease and to investigate possible advanced treatment options.

References: [1] A Gene-Based Association Method for Mapping Traits using Reference Transcriptome Data. Gamazon ER, Wheeler HE, Shah KP, Mozaffari SV, Aquino-Michaels K, Carroll RJ, Eyler AE, Denny JC; GTEx Consortium, Nicolae DL, Cox NJ, Im HK. Nat Genet. 2015 Sep;47(9):1091-8.
[2] Quantifying the Regulatory Effect Size of Cis-Acting Genetic Variation using Allelic Fold Change. Mohammadi P, Castel SE, Brown AA, Lappalainen T. Genome Res. 2017 Nov;27(11):1872-1884.

GTEx data are aiding researchers in uncovering how genetic alterations contribute to schizophrenia

Over the last decade researchers have discovered more than 100 genetic loci associated with schizophrenia diagnosis; however, determining how these variants alter biology and contribute to schizophrenia development has been more challenging. With the expansion of large genetics databases like GTEx and ENCODE, researchers are beginning to move beyond genome wide association studies to link genetic variation to alterations in gene expression and to more accurately determine the molecular basis of complex diseases like schizophrenia. In a recent paper from Nature Neuroscience, researchers reported that around 20% of the 108 previously known schizophrenia loci contain genetic variants that potentially contribute to altered gene expression in the brain, and thus could contribute to schizophrenia development. Furthermore, in five of the loci investigated the genetic variants were located in a single gene: FURIN, TSNARE1, CNTN4, CLCN3 and SNAP91. The researchers went on to demonstrate that three of those genes (FURIN, TSNARE1 and CNTN4) were involved in neurodevelopment in zebrafish, strengthening the evidence that they may also play an important role in human brain development and that their altered expression may be contributing to schizophrenia development. These discoveries were made possible by data from the CommonMind Consortium – a Public-Private partnership with a large brain sample collection – together with GTEx’s extensive collection of post-mortem brain donors and public set of expression quantitative trait loci from brain.

GTEx dataset helps researchers determine how gene duplications potentially lead to genes with new biological functions

A major source of new genes – which can lead to new biological functions through evolution – is through duplication of ancestral genes. Many genes function normally only when present as a single copy because the dosage of their resultant protein is tightly controlled. When a gene is duplicated the dosage is also duplicated, and in many instances this negatively affects survival and creates evolutionary pressure to restore gene dosage. In the majority of cases gene dosage is restored because the duplicated gene accumulates debilitating mutations rendering it nonfunctional – faster and more likely to occur. Occasionally, the duplicated gene will develop a new function that provides an evolutionary advantage which then spreads through the population – slower and less likely to occur. Since gene loss is favored over preservation, what mechanisms support the persistence of new gene duplicates long enough for new biological functions to evolve? Using the GTEx dataset Lan and Pritchard published an article in Science providing evidence that suggests new gene duplicates are preserved because gene expression from both copies is downregulated, restoring gene dosage. They suggest that since this reduces the evolutionary pressure for either duplicate to become nonfunctional, both genes can evolve independently over time.

Read a highlight of this exciting research on NIH director Dr. Francis Collins blog!

GTEx dataset helps researchers uncover biological functions for the small amount of Neandertal DNA present in modern humans

Following modern humans exodus from Africa ~60,000 years ago they encountered now-extinct Neandertals and on at least a few occasions interbreeding occurred. As a result, genomes of modern Eurasians contain ~1.5 to 4% Neandertal DNA. However, the contribution(s) of this DNA to modern human’s physiology and disease susceptibility/progression is only beginning to be understood. In a recent Science publication, Simonti and coworkers identified two single nucleotide polymorphisms (SNP) within the introgressed Neandertal DNA that were associated with disease. A SNP in the intron of P-selectin (SELP) was associated with a hypercoagulable state while a second upstream of stromal interaction molecule 1 (STIM1) was associated with incontinence, bladder pain, and urinary tract disorders. Because of the GTEx dataset they were able to show that both Neandertal SNPs are associated with changes in SELP (increased) and STIM1 (decreased) gene expression, suggesting that the effects from modern human-Neandertal interbreeding are still with us today.

GTEx hopes to play a role in uncovering how genetic alterations contribute to psychiatric disorders

Genome wide association studies (GWAS) have identified over 100 genetic loci associated with schizophrenia diagnosis. However, GWAS studies have limited ability to uncover how genetic loci associated with schizophrenia diagnosis alter biological processes resulting in risk for or protection from schizophrenia or whether those genetic loci associated with schizophrenia diagnosis are amenable to interventions. The GTEx program is optimistic that its sequence database containing over 900 post-mortem donors – over 420 of them whole brain donors – will help to untangle how the over 100 loci associated with schizophrenia diagnosis actually function in the progression of the disease. This week, a highly publicized Nature paper uncovered the biological basis for why the major histocompatibility complex locus, a GWAS-identified genetic loci spanning several megabases, is associated with schizophrenia diagnosis. With the aid of GTEx data from brain frontal cortex, the researchers showed that each common complement component 4A (C4A) allele associates with schizophrenia in proportion to its tendency to generate greater expression of C4A mRNA.

GTEx Perspective: Understanding how non-coding genomic polymorphisms affect gene expression 
Read a Washington Post article on the Nature paper
Read an NIH Press Release

GTEx Reaches Midpoint Milestone

The GTExPortal  was just updated! This latest version of sequence data encompasses roughly half of the anticipated 960 postmortem donors. This release includes genotype data from approximately 450 donors and over 9600 RNA-seq samples across 51 tissue sites and 2 cell lines, with adequate power to detect Expression Quantitative Trait Loci in 44 tissues. Full gene and isoform expression datasets are available for download through the GTEx Portal while genotypes and RNA-seq bam files are available via dbGaP.

GTEx Scientists Investigate Sex Differences.

Studying Sex DifferencesSex and gender play a role in how health and disease differ across individuals, and considering these factors during research informs the development of preventive and therapeutic interventions for both sexes. Learn how supplements to GTEx grants are enabling researchers to investigate sex as a biological variable.

Scientists Use GTEx Data to Help Predict Genes Associated with Disease

Hand with DNA ribbon wrapped around itResearchers at the University of Chicago and their collaborators have developed PrediXcan, a computational method that links genetic variation and gene activity to disease traits. The method uses gene activity datasets like the Genotype-Tissue Expression (GTEx) data to train the computer to associate certain genetic profiles with certain diseases. The technique has important implications for linking genetics to disease susceptibility.


A Gene-Based Association Method for Mapping Traits Using Reference Transcriptome Data. Eric R Gamazon, Heather E Wheeler, Kaanan P Shah, Sahar V Mozaffari, Keston Aquino-Michaels, Robert J Carroll, Anne E Eyler, Joshua C Denny, GTEx Consortium, Dan L Nicolae, Nancy J Cox & Hae Kyung Im. Nature Genetics. August, 2015. doi:10.1038/ng.3367. Read the article abstract.

Read an article describing the research.


New Resource Shows How Differences in DNA Affect Gene Activity and Disease Susceptibility

Tissue Sampling for the Genotype-Tissue Expression ProjectWe have known for many years that differences in the DNA that codes for our genes affect everything from our eye color to our susceptibility for certain diseases. Now we are finding that differences in genes are only part of the story. Differences in DNA that control when and how much genes are turned on and off can have a profound impact on health and disease. Researchers funded by the Genotype-Tissue Expression (GTEx) program have created a new data resource to help find out how differences in an individual’s genetic make-up can affect gene activity and contribute to disease.
Scientists can use the new resource to examine genes and gene regulation in many different types of human tissues at the same time. Investigators are collecting more than 30 tissue types from autopsy or organ donations and tissue transplant programs, and analyzing both DNA and RNA from samples. The project will eventually include tissue samples from about 900 deceased donors.

The resource is already beginning to bear fruit. One study looked at mutations called protein-truncating variants which shorten the protein-coding sequence of genes. Rare protein-truncating variants can lead to diseases like Duchenne muscular dystrophy. Most protein-truncating variants are harmless, and researchers found that each person’s genome carries about 100 of them. Another study looked at gene activity in a variety of tissues from multiple donors. Researchers found slightly fewer than 2,000 genes that vary with age, including genes related to Alzheimer’s disease. They also found more than 750 genes with differences in activity between men and women, with most in breast tissue.


The Genotype-Tissue Expression (GTEx) Pilot Analysis: Mutitissue Gene Regulation in Humans. The GTEx Consortium. Science, May 2015, Vol. 348 no. 6235 pp. 648-660. Read the article abstract

Read the NIH Press Release.

Read more about the Genotype-Tissue Expression (GTEx) program here.

A list of companion papers to the GTEx Pilot Analysis is available via the GTEx Portal website.

GTEx Project Expands Functional Studies of Genetic Variation

Eight Genotype-Tissue Expression grants will contribute to a resource database and tissue bank researchers can use them to study how inherited genomic variants — inherited spelling changes in the DNA code — may influence gene activity and lead to disease. Read the Press Release from the NIH National Human Genome Research Institute.

GTEx Biospecimens Access Policy Goes Live

In October of 2013, a mechanism was put in place to allow researchers access to banked GTEx biospecimens. The goal of this policy is to facilitate the efficient use of this valuable resource. Requests to access the biospecimens can be made either through a "Short" or "Full" Sample Availability/Access Request, depending on the size and scope of the project and whether grant funding for the work is already in place, among other factors. More information on the GTEx Biospecimens Access Policy and related forms can be found on the GTEx Portal Sample Request Forms page. The Access Policy can also be viewed directly here.

GTEx pilot project described as one of the most ambitious tissue-collection studies - Nature’s Technology Feature “Building Better Biobanks

The June 2012 issue of Nature, highlights efforts being made to store high-quality, data-rich biological samples that are essential for research. In the article, GTEx Coordinator Dr. Jeff Struewing, M.D., M.S. (NHGRI) and other members of the GTEx Working Group discuss the various steps throughout the collection process where attention to detail results in high-quality specimens.

Reference: Nature 2012 June; Volume 486 “

The Genotype-Tissue Expression (GTEx) project Commentary is featured in Nature Genetics

The June 2013 issue of Nature Genetics highlights the GTEx project published by the GTEx Consortium.



This page last reviewed on November 27, 2017