# Regulatory modifiers of coding variant penetrance via haplotype epistasis in human populations and diseases

> **NIH NIH R01** · NEW YORK GENOME CENTER · 2020 · $373,604

## Abstract

PROJECT ABSTRACT 
 
Variable penetrance is a phenomenon where the severity of the effect of a genetic variant differs among 
individuals who carry it. We propose to study a specific type of modified penetrance caused by genetic 
interaction or epistasis in humans, where a regulatory variant in cis modifies the penetrance of coding variants 
of the target gene. We call this phenomenon haplotype epistasis. We will study this phenomenon using genetic 
data of the general human population and of diseases with different genetic architectures. First, we will study 
signals of purifying selection against specific haplotype combinations as a proxy of phenotypically relevant 
epistatic effects. This will shed light on the modes and prevalence of haplotype epistasis, and the role of 
epistatic selection in shaping the spectrum of genetic variation in humans. Second, haplotype epistasis has 
been shown to affect genetic disease risk in some specific examples, but this mechanism is rarely considered 
in genetic studies that typically analyze genetic variants one-by-one. We aim to characterize haplotype 
epistasis as a potentially important phenomenon in rare variants contributing to autism risk, common variants 
predisposing to diverse traits mapped by genome-wide association studies, and germline modifiers of somatic 
cancer driver mutations. Furthermore, we will validate 5-10 examples of epistasis by genome editing of human 
cell lines, followed by cellular phenotyping. In summary, our study integrates many domains in human genetics 
that are usually studied in isolation. It is the first systematic characterization of haplotype epistasis and has 
potential to bring forward an important paradigm of epistatic functional effects of genetic variants.

## Key facts

- **NIH application ID:** 9926898
- **Project number:** 5R01GM122924-04
- **Recipient organization:** NEW YORK GENOME CENTER
- **Principal Investigator:** Tuuli Lappalainen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,604
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926898

## Citation

> US National Institutes of Health, RePORTER application 9926898, Regulatory modifiers of coding variant penetrance via haplotype epistasis in human populations and diseases (5R01GM122924-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9926898. Licensed CC0.

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