Predictive genomic medicine

NIH project aims to determine phenotype from genotype, match researchers to genes and variants of interest

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BETHESDA, Md.—To enable researchers to access data from huge genomic databases, contact individuals with genotypes of interest and investigate the health consequences of their genes and gene variants, the National Institutes of Health (NIH) and Inova Health System researchers have teamed up to launch a two-year pilot project. The Genomic Ascertainment Cohort (TGAC) will enable researchers to recall genotyped people and examine the genes and gene variants’ influence on their phenotypes, observable traits such as height, eye color or blood type.
Reversing the trend of examining traits or symptoms and then seeking genes or gene variants that cause or contribute to them, NIH will establish a new database of 10,000 human genomes and exomes, the 1 to 2 percent of the genome that contains protein-coding genes. Then NIH and Inova researchers aim to predict conditions that specific genes or gene variants might produce and test those predictions by re-examining individuals who donated their DNA sequence information to the database. TGAC, which will be based in the Washington, D.C., area, will limit participants to people who have consented to be re-contacted.
According to Dr. Leslie Biesecker, TGAC co-organizer and chief of the Medical Genomics and Metabolic Genetics Branch at NIH’s National Human Genome Research Institute (NHGRI)—which will host the database and administer the program—“We want to determine what genes and gene variants do and use this as a platform to test our ability to predict phenotype from genotype, one of the key underpinnings of predictive genomic medicine to improve or measure health.”
He added, “NHGRI is taking the lead, partnering with other NIH agencies. The project will be contributing to a super cohort of 10,000 people already sequenced and having given consent. Inova is the biggest contributor. Now we will be finding additional cohorts, aggregating the results, asking questions, seeing if we’re interested in the gene and finding the phenotype. We’ll be able to answer what the phenotype is efficiently using data already generated. Then we will put the data on the Genome Aggregation Database (gnomAD), a resource developed by an international coalition of investigators, with the goal of aggregating and harmonizing both exome and genome sequencing data from a wide variety of large-scale sequencing projects and making summary data available for the wider scientific community.”
Participating NIH institutes will each contribute genome and exome sequences from existing research programs to the database, including NHGRI’s CLINSEQ program, healthy bone marrow donors from the National Heart, Lung, and Blood Institute’s transplant program, the National Institute of Environmental Health Sciences Environmental Polymorphism Study, and others. Inova will contribute the genome sequences of 8,000 people in parent-child trios from its Longitudinal Childhood Genome Study. The duration of the program will depend on its success.
According to Dr. Richard Siegel, who is the TGAC co-organizer as well as clinical director and chief of the Autoimmunity Branch at NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), “Ten thousand genomes and exomes is our initial goal because that will allow recruitment of individuals with both common and rarer gene variants. This is large-scale sharing of data and research volunteers. We will be taking already sequenced cohorts and making them available to large numbers of researchers.”
If a researcher locates a genotype of interest in the database and the request is approved, the researcher may ask participants with the genotype to come to the NIH Clinical Center. Most researchers’ requests will require simple blood samples from participants. Other tests might include electroencephalograms (EEG) or MRI scans.
“This is essentially matchmaking between genes and gene variants and the researchers who study them,” said Siegel. “We hope they’ll provide insights that haven’t been possible until now. If successful, we plan to open the database to outside researchers in the future.”
NHGRI is one of the 27 institutes and centers at the National Institutes of Health. The NHGRI Extramural Research Program supports grants for research, and training and career development at sites nationwide.
The initial investment will be $600,000 for the first year, leveraging resources already set up through the Intramural Research Program that is all paid for and scientifically valid, according to Biesecker. “The NIH Clinical Center is paid for in fixed fees. It is a huge advantage not to have to do studies in clinical settings. It could be horrifically expensive. It’s a resource there to be used, and it will benefit researchers everywhere,” he noted.

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