# Dissecting dynamic genetic effects from thymus development to immune-mediated disease

> **NIH NIH R01** · COLD SPRING HARBOR LABORATORY · 2022 · $587,919

## Abstract

PROJECT SUMMARY: Imbalance of immune and inflammatory activity is a hallmark of immune-mediated dis-
eases. Genome-wide association studies have identified hundreds of loci that increase susceptibility to immune-
mediated diseases. Functional effects of these genetic variants are difficult to infer as they might only impact a
particular cell type and their effects may be restricted to specific points in development. Studies on adult immune
cells have shed light on mediator cells and mechanisms of disease-associated variants, however, childhood is a
critical yet understudied stage in the development of the immune system. Genetic determinants of T cell develop-
ment and effector function during childhood have not been studied and their role in immune-mediated diseases
is unknown.
We propose to fill gaps that link the genetics of immune-mediated diseases to their effector cells, developmen-
tal stages, and mechanisms. Our goals are 1) to understand the importance of genetically mediated T
cell development and central tolerance induction on immune-mediated diseases and 2) to identify the
importance of childhood immune phenotypes on disease in adulthood.
To reach these goals, we propose studying the dynamic genetic influences of human T cell development using
single-cell gene expression quantitative trait mapping in human pediatric thymus samples. To study the genetics
of the progression from development to peripheral effector function, we will collect peripheral immune cells from
the same pediatric patients. Furthermore, we will study genetic effects on pediatric immune cells in different
activation states to pinpoint genetic effects acting upon stimulation. To investigate genetic effects on immune
cells at different ages, we will integrate the genetic effects we identify in pediatric immune cells with those derived
from adult and neonatal cells from other studies. Lastly, we will examine genetic effects on central and peripheral
immune phenotypes in the context of immune-mediated diseases. We will generate profiles of chromatin accessi-
bility in thymus and peripheral immune cells to identify regulatory mechanisms in chromatin. This will allow us to
conduct colocalization studies of immune-mediated disease variants, immune cell-associated variants and open
chromatin regions. We will then estimate causality of immune phenotypes on immune-mediated diseases using
a Mendelian Randomization framework.
In summary, our research offers an innovative approach to study complex disease mechanisms: it combines
quantitative genetics and immunology using clinical specimens to generate new insights into the genetics of
immune-mediated diseases, their effector cells and molecular mechanisms. This mechanistic understanding of
disease-associated variants is fundamental for advancing towards novel treatments of immune-mediated dis-
eases.

## Key facts

- **NIH application ID:** 10412413
- **Project number:** 1R01AI167862-01
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** Hannah Verena Meyer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $587,919
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412413

## Citation

> US National Institutes of Health, RePORTER application 10412413, Dissecting dynamic genetic effects from thymus development to immune-mediated disease (1R01AI167862-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10412413. Licensed CC0.

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