Integrating frequency and phenotypic association data to improve interpretation of rare genetic variants
Active Project Grant Awarded Last action
- Award ID
- R35GM157035
- Recipient
-
The General Hospital Corporation UEI FLJ7DQKLL226
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $825,000
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date 25% complete
- Place of performance
- Boston, MA 02114, USA
Award details come from USAspending.gov.
Description
- Abstract
- At present, the diagnoses of many rare disease patients remain unsolved and the effects of rare variants in common diseases remains unclear. Further, the phenotypic effects of most high-impact mutations are unknown. Accurate methods to interpret genetic variants would enhance many aspects of biomedical research, including genome-wide association studies and functional studies, as well as clinical diagnostics of rare disease patients. In my laboratory, we build tools, methods, and resources to interpret genetic variation that are applicable in clinical practice and human disease research. Beginning with predicted loss-of-function variants, we have built a widely used annotation tool, loftee, that is highly specific in identifying variants triggering nonsense- mediated decay. I have aggregated massive datasets of human genomes and exomes (gnomad) to build the largest variant frequency maps released to the public, for clinical laboratories and researchers interpreting disease variation. Finally, i have performed massive-scale common and rare variant association analysis on thousands of phenotypes using mixed models to describe the most robust estimates of variant-phenotype associations, powering gene discovery for common diseases. Using state-of-the-art computational methods, this research program will improve the interpretation of variants in the human genome, improving current annotation methods for predicted loss-of-function, missense, and non-coding mutations, incorporating information from genetic reference data as well as biobanks with genome and disease/phenotype data. My research program will build a framework for assessing function for many classes of deleterious variants by integrating frequency data from diverse populations into deep learning frameworks. Finally, this project will integrate rare variant association data into deep learning models to identify loss-of-function-like missense variants. In this way, my research program will improve interpretation of genetic variants found in patients and large cohorts and biobanks, improving clinical genetic practice and human disease research.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $412,500 | |
| Original award | $412,500 |
Quick answers
Who received award R35GM157035?
R35GM157035 was awarded to The General Hospital Corporation by National Institute of General Medical Sciences (National Institutes of Health) on August 15, 2025.
How much is award R35GM157035 worth?
$825,000 has been obligated on R35GM157035.
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