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Lessons Learned From NHLBI Exome Project

November 8, 2012

The search for rare gene variants associated with heart, lung and blood-related disease traits, as well as those of public health importance found that 1.1 million of the 1.2 million such variants within exomes occur very infrequently, said a Baylor College of Medicine expert in the analysis of such findings in a plenary abstract session at the annual meeting of the American Society of Human Genetics (exomes are the part of the genome that contain
protein-coding genes.)

“They were often observed in only one person,” said Dr. Suzanne Leal, professor of molecular and human genetics and director of the Center for Statistical Genetics at Baylor College of Medicine in Houston, Texas. “Most of the observed variants occurred in specific populations–either European or African-American. Of the identified variants, about 720,000 changed the genetic code in a manner that could produce flawed proteins. Yet the role played by most of these variants in disease development has not been established.”

Mixed results

Leal presented results from the National Heart, Lung and Blood Institute Exome Sequencing Project in a plenary session at the meeting. The multi-institutional project took samples from several large studies, eventually producing data from the exomes (the protein-coding part of the genome), of 6,700 individuals 4,420 European Americans and 2,312 African Americans. They chose samples-based specific traits such as extremely high or low bad cholesterol (low density lipoprotein) or blood pressure as well as for specific problems such as early heart attack, stroke or chronic obstructure pulmonary disease. They also chose individuals whose symptoms and medical history were extensively documented.

Then they evaluated the people in the study for more than 80 traits such as electrocardiogram measurements, good cholesterol (high density lipoprotein), bad cholesterol, red blood cell count, etc.

Results from the study have been mixed. Sequencing the exomes of 91 patients with cystic fibrosis discovered that variants in a particular gene (DCTN4) were associated with the time at which a patient developed an airway infection with an organism called Pseudomonas aeruginosa. The researchers also replicated associations between individual DNA variants and traits such as high levels of bad cholesterol and C-reactive protein, which is associated with inflammation. These were mainly findings associated with common variants.

New field

This exome sequencing study aggregated information from individual variants within a particular disease to tease out association between traits and rare variants. In one case, they detected an association with rare variants in the APOC3 gene that lowers the levels of triglycerides, unhealthy fats in the blood, said Leal.

“In many cases, data from the Exome Sequencing Projects gave us leads that had to be evaluated using more study subjects,” said Leal. One way to do this was to use the exome chip, which contains approximately 240,000 coding variants. The Exome Sequencing Project contributed much of the information used to develop the chip, she said.

“This is a very new field for which new methodology had to be developed. We learned many lessons in the quality control and analysis of exome data, as well as what types of results one would expect to see when analyzing rare variants. Additionally the Exome Sequencing Project has been extremely valuable in obtaining a better understanding of population genomics and the history of man,” Leal said.

The exome sequence variant data is publically available on the Exome Variant Server. Additionally phenotype and exome data can be requested from the NIH repository dbGaP.

The Exome Sequencing Project, sponsored by NHLBI, included researchers at the Broad Institute of MIT and Harvard University, Cambridge, Mass.; University of Washington, Seattle; Ohio State University Medical Center, Columbus; University of Virginia Health System, Charlottesville; Fred Hutchinson Cancer Research Center, Seattle, Wash.; Stanford University, Stanford, Calif.; University of Michigan, Ann Arbor; University of Vermont, Burlington; University of North Carolina, Chapel Hill; and BCM.

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