GTEx findings reveal new insights into how DNA differences influence gene activity, disease susceptibility

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Researchers funded by the National Institutes of Health Genotype-Tissue Expression (GTEx) project have created a new and much-anticipated data resource to help establish how differences in an individual’s genomic make-up can affect gene activity and contribute to disease. The new resource will enable scientists to examine the underlying genomics of many different human tissues and cells at the same time, and promises to open new avenues to the study and understanding of human biology.

Matthew Stephens, PhD, professor of human genetics and statistics

Matthew Stephens, PhD, professor of human genetics and statistics

University of Chicago faculty Matthew Stephens, PhD, professor of human genetics and statistics, Dan Nicolae, PhD, professor of medicine, human genetics and statistics, and former UChicago professor Nancy Cox, PhD, now at Vanderbilt,  lead teams on the project as part of the GTEx Consortium Analysis Working Group (AWG), which performed the statistical analysis and interpretation of the data.

“We want to understand the genetic mechanisms and genes that govern the different cell types and tissues in our body,” Stephens said. “This can help understand the biology of disease, because diseases are often the result of problems with a specific tissue or cell type.”

GTEx investigators reported initial findings from a two-year pilot study in several papers appearing online May 7, 2015, in Science and other journals. These efforts provide new insights into how genomic variants — inherited spelling differences in the DNA code — control how, when and how much genes are turned on and off in different tissues, and can predispose people to diseases such as cancer, heart disease and diabetes.

Dan Nicolae, PhD, professor of medicine, human genetics and statistics

Dan Nicolae, PhD, professor of medicine, human genetics and statistics

“The GTEx project will help answer fundamental questions about the genetic architecture of human traits by integrating the rich cross-tissue information obtained in GTEx with data from many other genetic studies,” said Nicolae. “It will provide insights into the mechanisms of gene regulation and its role in disease risk, help us understand system-level differences between cell types and aid in the development of novel algorithms for analyzing genetic data with a long-term focus on personalized medicine.”

NIH launched the GTEx Project in 2010 to create a data resource and tissue bank for scientists to study how genomic variants may affect gene activity and disease susceptibility. Investigators are collecting more than 30 tissue types from autopsy and organ donations in addition to tissue transplant programs. The DNA and RNA from those samples are then analyzed using cutting-edge genomic methods. The project will eventually include tissue samples from about 900 deceased donors.

In the main Science paper, researchers analyzed the gene activity readouts of more than 1,600 tissue samples collected from 175 individuals and 43 different tissues types. One way that researchers evaluate gene activity is to measure RNA, which is the readout from the genome’s DNA instructions. Investigators focused much of their analyses on samples from the nine most available tissue types: fat, heart, lung, skeletal muscle, skin, thyroid, blood, and tibial artery and nerve.

The genomic blueprint of every cell is the same, but what makes a kidney cell different from a liver cell is the set of genes that are turned on (expressed) and off over time and the level at which those genes are expressed. GTEx investigators used a methodology — expression quantitative trait locus (eQTL) analysis — to gauge how variants affect gene expression activity. An eQTL is an association between a variant at a specific genomic location and the level of activity of a gene in a particular tissue. One of the goals of GTEx is to identify eQTLs for all genes and assess whether or not their effects are shared among multiple tissues.

Investigators discovered a set of variants with common activity among the different tissue types. In fact, about half of the eQTLs for protein-coding genes were active in all nine tissues. They identified approximately 900 to 2,200 eQTL genes – genes linked to nearby genomic variants — for each of the nine tissues studied, and 6,486 eQTL genes across all the tissues.

Comparing tissue-specific eQTLs with genetic disease associations might help provide insights into which tissues are the most relevant to a disease. The researchers also found a great deal of eQTL sharing among tissues, which can help explain how genomic variants affect the different tissues in which they are active.

Even when active in multiple tissues, the same variant can sometimes have a different effect in different tissues. GTEx researchers found, for example, that a variant that affects the activity of two genes associated with blood pressure had a stronger effect on gene expression relevant to blood pressure in the tibial artery – even though there was greater overall gene activity in other tissues. They also noted that the same gene activity profiles characterizing tissues from living donors were seen in the GTEx samples from deceased donors.

Additional UChicago researchers involved in the GTEx project include Barbara Stranger, PhD, assistant professor of medicine, Hae Kyung Im, PhD, Research Associate (Assistant Professor) in medicine, and Lin Chen, PhD, assistant professor of public health sciences. Former UChicago professor Jonathan Pritchard, PhD, now at Stanford, led a team as well. Additional former UChicago researchers Eric Gamazon and Anuar Konkashbaev, now at Vanderbilt, Timothée Flutre, PhD, at the Institut National de la Recherche Agronomique, and Xiaoquan Wen, PhD, now at the University of Michigan contributed.

This work was supported by the NIH Common Fund and the following NIH grants:  R01 DA006227-17, R01 MH090941, R01 MH090951, R01 MH090937, R01 MH090936, R01 MH090948, R01 GM104371, R01 AG046170, R01 CA163772 and U01AI111598-01. Additional funding was provided by the European Research Council, the Swiss National Science Foundation and Louis-Jeantet Foundation, the Wellcome Trust, the Clarendon Scholarship, the NDM Studentship and the Green Templeton College Award.

About Kevin Jiang (147 Articles)
Kevin Jiang is a Science Writer and Media Relations Specialist at the University of Chicago Medicine. He focuses on neuroscience and neurosurgery, orthopedics, psychology, genetics, biology, evolution, biomedical and basic science research.
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