# Haplotype-aware models of gene and isoform expression with application to genetic studies of disease in diverse populations

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $657,226

## Abstract

Project Summary
In recent years, there has been a deluge of data from genome-wide functional assays. Rapid expansion of
computational techniques for mapping genetic correlates of intermediate molecular traits, such as gene
expression, has offered opportunities to explore molecular mechanisms that underlie disease susceptibility. Here
we will develop mechanistically justified statistical methods that enable allele-specific assessment of regulatory
activity in individual genomes. We hypothesize that incorporating the dosage modifying effect of regulatory
alleles into genetic association analyses will enhance the resolution of the current genotype-phenotype maps,
and allow for a more refined mapping of the underlying biological mechanisms.
Our proposal is organized into the following aims:
Aim1: To derive biologically interpretable effect sizes for regulatory variants and to enable allele-specific
prediction of gene and isoform dosage, we will develop haplotype-aware models of genetic regulatory
variation and apply them to large-scale reference transcriptome datasets.
Aim2: To enhance the resolution of the current genotype-phenotype maps, we will develop genetic association
methods that incorporate expected allele dosages for genes and transcript isoforms and apply them to
large biobank and GWAS data.
Aim3: To improve generalizability of genetic association signals to understudied populations, we will develop
genetic association methods that incorporate population-specific regulatory architecture of genes and
transcript isoforms.

## Key facts

- **NIH application ID:** 10101773
- **Project number:** 1R01GM140287-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Eric R Gamazon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $657,226
- **Award type:** 1
- **Project period:** 2021-03-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10101773

## Citation

> US National Institutes of Health, RePORTER application 10101773, Haplotype-aware models of gene and isoform expression with application to genetic studies of disease in diverse populations (1R01GM140287-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10101773. Licensed CC0.

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