# Variant-to-gene mapping for brain related traits and disorders

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2022 · $479,827

## Abstract

Project Summary
Since the completion of the Human Genome Project and the HapMap Project, genetic science has identified a
wealth of associations between common or rare variants and human complex traits, including diseases. GWAS
has arguably been the most successful tool in this so called “post-genomic” era, yielding almost 200,000 robust
associations between common SNPs and more than 5,000 human traits. However, because of linkage
disequilibrium, GWAS only report genomic “signals” or “loci” tagged by index SNPs and not the underlying true
causal variants. Even more crucially, GWAS cannot indicate the effector genes at these loci, which are necessary
to translate these findings into development of new therapies for disease. The main challenges to identifying
causal variants and effector genes are that 1) the majority of variants identified by GWAS reside in non-coding
regions of the genome and are thought to regulate gene expression, often hundreds of kb away in linear distance
and 2) gene expression regulation is exquisitely tissue and cell type specific. While consortia such as ENCODE
and GTEx have already built high quality, publicly available genome-wide datasets for many epigenetic markers
and gene expression in different tissues and cell types, some limitations exist such as the number and
heterogeneity of cell and tissue types available, the use of post-mortem samples, and the limited power due to
the large sample number needed for QTL studies. As an alternative approach, I propose a variant-to-gene
mapping campaign based on genome-wide high-resolution, promoter-focused Capture C, a technique that
detects contacts between different regions of the genome in 3D space. Coupled with other genomic techniques,
i.e. ATAC-seq, ChIP-seq and RNA-seq, this approach will allow us to identify putative causal variants residing
in open chromatin and with enhancer signatures, and their (transcriptionally active) effector genes (including
non-coding RNAs). Importantly, this proposal will focus on brain-related traits and disorders, a field where many
GWAS signals have been reported, but only a few have been definitely linked to their effector genes, including
many neurodegenerative disorders still lacking effective therapies. Using a tractable in vitro model system such
as human iPSC-derived neural cell types (neurons, astrocytes and microglia, including co-cultures and brain
organoids), I will be able to incorporate a temporal and functional dimension to these studies, which will help us
identify mechanisms of disease etiology and progression in neuro-developmental and neurodegenerative
disorders. Importantly, the functional genomics studies proposed will be performed in cell lines derived from
individuals of different sex and ethnicity, to explore sex and ethnicity -specific differences in gene regulation.

## Key facts

- **NIH application ID:** 10487477
- **Project number:** 5R35HG011959-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Alessandra Chesi
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $479,827
- **Award type:** 5
- **Project period:** 2021-09-10 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487477

## Citation

> US National Institutes of Health, RePORTER application 10487477, Variant-to-gene mapping for brain related traits and disorders (5R35HG011959-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10487477. Licensed CC0.

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