# Predicting the impact of genetic variants, genes and pathways on human Disease

> **NIH NIH U01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $409,010

## Abstract

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. But 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 data sets 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 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 diseases 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 casual 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 effect, 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 publicati...

## Key facts

- **NIH application ID:** 10296867
- **Project number:** 1U01HG012009-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** ALKES L PRICE
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $409,010
- **Award type:** 1
- **Project period:** 2021-09-07 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296867

## Citation

> US National Institutes of Health, RePORTER application 10296867, Predicting the impact of genetic variants, genes and pathways on human Disease (1U01HG012009-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10296867. Licensed CC0.

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