# Investigating the role of transcription factors in the context variability of genetic variant effects

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $37,424

## Abstract

PROJECT SUMMARY
 The Genotype Tissue Expression (GTEx) Consortium has identified thousands of expression quantitative
trait loci (eQTLs) in the human population that affect gene expression in multiple tissues. These regulatory
variants are enriched in cis-regulatory elements and co-localize with GWAS loci, implying that many eQTLs act
via non-coding mechanisms to impact human phenotype and possibly cause disease. Current research efforts
suggest that noncoding eQTLs’ effects on gene expression are primarily mediated by altered transcription factor
(TF) binding affinity. Long-term objective: Given the biological relevance of tissue in disease phenotypes and the
impact of environmental effects on cell state on disease penetrance, understanding the context variability of
eQTLs is crucial for unraveling their genetic contributions to complex traits and disease. Central hypothesis:
Since TF activity levels vary among cell types and between individuals, I hypothesize that the observed context
variability of many eQTLs is explained by varying TF levels. Research design and methods: I propose to use the
natural variation of TF activity among tissues and between individuals to elucidate mechanisms of action of eQTL
regulatory variants and understand context specificity of eQTL effects. I will then exploit these mechanisms to
understand tissue variability and gene-by-environment interactions of GWAS effects. To do so, I will use data
from the GTEx Consortium v8 release, which includes 838 individuals’ whole genome sequences and their RNA-
seq data from a total of 15,201 samples across 49 tissues. Specific aims: In Aim 1, I will characterize tissue-
variable mechanisms of eQTLs and their application to human disease, which will discover upstream trans-acting
regulators of a subset of eQTLs and will propose causal mechanisms and trans-regulators of GWAS loci. Aim 2
focuses on eQTL differences between individuals and environmental modifiers of eQTL effects, and I will use
these analyses to identify gene-by-environment interactions of common diseases and complex traits. My
proposed research will elucidate mechanisms of actions and trans-regulators of specific eQTLs and GWAS loci,
and it will discover gene-by-environment interactions that affect disease penetrance. It promises a deeper
understanding of gene regulation and of genetic and environmental contributions to complex traits and disease.
Fellowship training plan: My proposed research training plan allows me to capitalize on my strengths and
previous experiences, and it will improve my skills in statistics and computational genomic data analysis, as well
as in study design, critical thinking, communication, mentorship, leadership, and professional development.
Environment: During my training plan, I am able to benefit from multiple research communities, including my
sponsor’s (Dr. Tuuli Lappalainen), lab, my cosponsor’s (Dr. Harmen Bussemaker) lab, the New York Genome
Center, the Columbia Integrated PhD P...

## Key facts

- **NIH application ID:** 10085997
- **Project number:** 5F31HG010580-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Elise Duboscq Flynn
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $37,424
- **Award type:** 5
- **Project period:** 2020-01-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085997

## Citation

> US National Institutes of Health, RePORTER application 10085997, Investigating the role of transcription factors in the context variability of genetic variant effects (5F31HG010580-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10085997. Licensed CC0.

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