# Variant to gene mapping for Alzheimer's Disease

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $725,237

## Abstract

ABSTRACT
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that impacts in excess of 5 million
Americans over the age 65 years old. AD disrupts memory and cognitive abilities, and there are currently no
effective therapies able to slow or halt its progression. Although environmental and lifestyle factors have been
implicated in its pathogenesis, AD is considered a complex disorder with a clear genetic component.
Intense genome wide association study (GWAS) efforts through large-scale collaborations have been
successful in discovering genetic loci robustly associated with AD beyond the classic APOE locus. However,
GWAS only reports genomic signals associated with a given trait and not necessarily the precise localization of
culprit genes. As such, over the past ten years, GWAS has not strictly represented a decade of gene target
discovery, rather it has simply been a decade of signal discovery.
One clear example of this is highlighted by the recent progress in characterizing the FTO locus in obesity. The
GWAS signal that resides within an intronic region of FTO has in fact been recently shown to primarily
influence the expression of the IRX3 and IRX5 genes nearby rather than the `host' gene itself, suggesting that
this variant is in an enhancer embedded in one gene but influencing the expression of others. So a key
question remains: is this the case with AD association signals as well?
Indeed, we have already addressed the most significant GWAS finding in type 2 diabetes reported to date,
namely genetic variation within the transcription factor 7-like 2 (TCF7L2) gene, which the P.I. on this
application first described in 2006. Through the use of chromatin conformation capture and CRISPR/Cas9
genome editing techniques, we have evidence that a culprit gene at this locus is ACSL5.
Since we already have a dedicated infrastructure in place to conduct such `variant to gene mapping' efforts,
including CHOP's established Human Pluripotent Stem Cell core, our team is poised to determine how GWAS-
implicated AD loci affect the expression and function of specific genes during neurodegeneration within
corresponding topologically associated domains (TADs). The application of `3D Genomics' and CRISPR based
techniques in the relevant cellular models of iPSC-derived neural progenitor cells (NPCs) and terminally
differentiated neurons is particularly timely, as it will aid in pinpointing causal gene(s) at established AD GWAS
signals when combined with `Assay for Transposase Accessible Chromatin sequencing' (ATAC-seq) to
ascertain a shortlist of putative causal SNPs, which will almost entirely be non-coding, and that coincide with
open chromatin.
Only by uncovering the causative genes related to GWAS-identified genetic variants, and understanding how
they operate, can we truly translate these high value GWAS reports in to meaningful benefits for patient care.

## Key facts

- **NIH application ID:** 9965708
- **Project number:** 5R01AG057516-04
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Struan F A Grant
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $725,237
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965708

## Citation

> US National Institutes of Health, RePORTER application 9965708, Variant to gene mapping for Alzheimer's Disease (5R01AG057516-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9965708. Licensed CC0.

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