U01HG012009

Predicting the Impact of Genetic Variants, Genes, and Pathways on Human Disease - Project Summary

Over the past decade, genome-wide association studies have discovered complex disease-associated genetic variants, while at the same time, whole genome sequencing studies have been identifying risk alleles for Mendelian and complex diseases. These variants have the potential to shed light on human disease mechanisms. However, there are several important challenges.

More than 90% of complex disease-associated variants lie within non-coding regions, posing a challenge of identifying relevant cell types and cell states, target genes, and regulatory mechanisms. The important task of linking these variants to genes itself can be challenging. In addition, as our ability to identify de novo and rare mutations for complex and Mendelian diseases is rapidly expanding, defining the function of those de novo alleles, which genes and pathways they affect, remains uncertain.

To address these challenges, we will predict the functional impact of disease risk variants at the level of individual variants, individual genes, and pathways to elucidate disease biology. In all aims of this proposal, we will utilize IGVF functional genomic data.

In Aim 1, we will predict the regulatory potential of variants in disease-critical cell types/states at a single base-pair resolution. We will identify pathogenic cell states by analyzing single-cell transcriptional datasets in a disease context, and then integrate single-cell epigenetic data to define the regulatory landscape of these rare disease cell states. These regulatory regions identified in this analysis can be used to annotate variants for potential function. Finally, to understand the functionality of specific variants in regulatory regions, we quantify selective pressure using large-scale whole genome sequencing data.

In Aim 2, we will predict functional impacts of genes by effectively linking variants to genes. Defining causal disease genes is critically important since they may be important for therapeutic targeting. We develop strategies to use genetic data and functional genomic data to predict downstream genes and evaluate these methods with a set of gold-standard causal genes from Mendelian phenotypes.

In Aim 3, we focus on rare and de novo mutations with large effect sizes. Here we recognize that predicting the function of these alleles requires an understanding of the pathways they affect, models to connect rare non-coding variants to genes, and strategies to define functionality of the variants based on population genetic parameters.

In Aim 4, we develop a framework to synergize with the IGVF consortium to advance consortium goals, outlining our integration plan and flexible programmatic framework.

The proposal represents a collaboration between Drs. Soumya Raychaudhuri, Alkes Price, and Shamil Sunyaev, bringing analytical expertise across functional genomics, single-cell data integration, and population genetics. These investigators have a history of successful collaborations with a strong publication record integrating functional genomics data with GWAS and sequencing studies to uncover disease mechanisms.

Brigham & Womens Hospital

NHGRI SUPPORTS THE DEVELOPMENT OF RESOURCES AND TECHNOLOGIES THAT WILL ACCELERATE GENOME RESEARCH AND ITS APPLICATION TO HUMAN HEALTH AND GENOMIC MEDICINE. A CRITICAL PART OF THE NHGRI MISSION CONTINUES TO BE THE STUDY OF THE ETHICAL, LEGAL AND SOCIAL IMPLICATIONS (ELSI) OF GENOME RESEARCH. NHGRI ALSO SUPPORTS THE TRAINING AND CAREER DEVELOPMENT OF INVESTIGATORS AND THE DISSEMINATION OF GENOME INFORMATION TO THE PUBLIC AND TO HEALTH PROFESSIONALS. THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM IS USED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM IS USED TO FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.172 - Human Genome Research

National Human Genome Research Institute (NHGRI) [HHS - NIH]

Boston, Massachusetts 021155727 United States

Single Zip Code

Developing Predictive Models of the Impact of Genomic Variation on Function (U01 Clinical Trial Not Allowed) (RFA-HG-20-047)

Amendment Since initial award the total obligations have increased 764% from $409,010 to $3,533,211.