NIH launches Genotype-Tissue Expression project

The National Institutes of Health recently announced awards to support an initiative to understand how genetic variation may control gene activity and its relationship to disease. Launched as a pilot phase, the Genotype-Tissue Expression (GTEx) project will create a resource researchers can use to study inherited susceptibility to illness and will establish a tissue bank for future biological studies.

Each cell in the human body contains a complete set of genes, yet not every gene is turned on, or expressed, in every cell in the body. To function properly, each type of cell turns different genes on and off, depending on what the cell does. For example, some genes that are turned on in a liver cell will be turned off in a heart cell.

In addition, recent genome-wide association studies have identified several hundred common genetic variants — inherited changes in the DNA sequence of the human genome — that play a role in an individual's susceptibility to complex human illnesses such as heart disease, mental illnesses, cancer and diabetes.

GTEx seeks to combine these two observations to generate data to study systematically how gene expression is regulated in different organs in the human body. This would be a key step to explain the underlying biology of many organ-specific diseases.

GTEx launches as a two-year pilot study supported by the NIH Common Fund.

Researchers will use GTEx data to follow up on findings from genome-wide association studies and as a resource for the general study of gene expression networks.

For instance, a researcher interested in cardiovascular disease could access GTEx data to view all the genetic variants in the human genome that affect gene expression in the heart. For particularly promising genes whose expression is correlated with a disease-associated genetic variant, functional studies in model organisms — such as mouse models of the disease — could then be targeted to further explore the mechanism by which genetic variants increase the risks of illness.

"GTEx will begin to provide researchers with a comprehensive view of genetic variation and a more precise understanding of how it affects genes critical to the normal function of tissues and organs," said NIH Director Francis S. Collins, M.D., Ph.D. "This resource will add a new dimension to our understanding of human biology and the mechanisms that lead to disease."

GTEx's initial phase will test the feasibility of collecting high-quality ribonucleic acid (RNA) from 30 to 50 tissue sites in the body, including the brain, lung, heart and muscle. A particular form of RNA, called messenger RNA, is a direct measure of gene expression.

Samples will come from approximately 160 deceased donors identified through autopsy or organ and tissue transplant programs. In addition, a small subset of normal tissues will be collected from living surgery patients as a comparison group. Extensive clinical and medical information for all GTEx donors will also be collected.

The DNA from each donor will be genotyped, a process that catalogs genetic variants across an individual's genome. Then, using 'next-generation sequencing' technologies, the RNA in each individual’s tissues will be sequenced using a new technique that accurately and comprehensively measures the level of gene expression.

"This kind of study is now possible because of recent advances in DNA sequencing technologies and analytical tools" said National Human Genome Research Institute (NHGRI) Director Eric D. Green, M.D., Ph.D., who is co-chair of the GTEx project. "GTEx will allow us to gain unprecedented insights into the influence of genetic variation on human health."

The GTEx pilot project comprises three biospecimen source sites, and a laboratory data analysis and coordinating center. Led by the National Cancer Institute's cancer Human Biobank (caHUB), http://cahub.cancer.gov/initiative, the biospecimen source sites will recruit donors and collect the tissues.