Integrative modelling of single-cell data to elucidate the genetic architecture of complex disease
Active Project Grant Awarded Last action
- Award ID
- R01HG013083
- Recipient
-
Dana-Farber Cancer Institute, Inc. UEI DPMGH9MG1X67
- Awarding agency
-
National Human Genome Research Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,547,119
Award facts
- Assistance listing
- 93.172 Human Genome Research
- Completion date 60% complete
- Place of performance
- Boston, MA 02215, USA
Award details come from USAspending.gov.
Description
- Abstract
- Leveraging genome wide association studies (gwas) to understand disease has proven challenging, as the underlying biological mechanisms are often poorly captured by bulk tissues. Recent advances in single-cell sequencing have led to a torrent of data across multiple modalities, contexts, and individuals, which provide an unprecedented opportunity to understand disease biology at high resolution. We hypothesize that the fine-scale cellular contexts captured by single-cell data will be effective at explaining disease heritability and fine-mapping disease mechanisms. However, current approaches to integrate single-cell data with gwas largely rely on off- the-shelf approaches developed for bulk sequencing, which obscure the rich phenotypic diversity present in individual cells within and across canonical cell types. The sparse and highly variable nature of single-cell data has additionally posed challenges for robustly identifying single-cell quantitative trait loci (QTL). Single-cell data continues to increase in size and complexity, emphasizing the need for scalable integrative modeling. Here, we propose a 5 year research plan to develop novel approaches for integrating single-cell data with gwas by modeling complex cellular phenotypes not captured by existing bulk approaches. Our proposal will identify novel disease-relevant cell states; leverage multiple single-cell modalities to fine-map disease variants and their target genes; and discover novel single-cell qtls associated with disease. Our specific aims are: aim 1: leveraging single-cell epigenetic data to identify heritable components of disease; aim 2: leveraging single-cell data to fine- map disease variants and their mechanisms; aim 3: defining the regulatory effects of disease variants using population-scale scrna-SEQ. While our proposed approaches are broadly applicable to common diseases, we will benchmark them on immune-related traits and neuropsychiatric traits which we have studied extensively with bulk datasets in published work and where we have now aggregated a large collection of relevant single-cell datasets. Our collaboration has multiple strengths: our focus on functional data integration across multiple single- cell modalities; our broad statistical and computational expertise; and our extensive, data-driven publication record on common disease.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $502,740 | |
| Amendment | $502,740 | |
| Amendment | $502,740 | |
| Amendment | $24,403 | |
| Amendment | $507,248 | |
| Original award | $507,248 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| President And Fellows Of Harvard College | $136,445 | |
| Brigham & Womens Hospital Inc. | $173,666 | |
| President And Fellows Of Harvard College | $128,401 | |
| Brigham & Womens Hospital Inc. | $163,427 |
Quick answers
Who received award R01HG013083?
R01HG013083 was awarded to Dana-Farber Cancer Institute, Inc. by National Human Genome Research Institute (National Institutes of Health) on August 1, 2024.
How much is award R01HG013083 worth?
$2,547,119 has been obligated on R01HG013083.
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