# Functional genomic studies in diverse populations to characterize risk loci for Alzheimer Disease

> **NIH NIH U01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $1,381,687

## Abstract

PROJECT SUMMARY
Genome Wide Association Studies (GWAS) studies in AD have been very successful in identifying genetic
regions contributing to the disease, but almost all have been in Non-Hispanic Whites (NHW). Most of these
associated genetic regions lie in non-coding, regulatory areas of the genome. That means to understand how
these associated loci influence the risk of getting AD, we must understand the regulatory architecture of the
genome in these associated regions. Recent efforts from our group and others have sought to understand the
genetic underpinning of AD in diverse, admixed populations such as African Americans (AA) and Hispanics (HI).
These studies have shown that different ethnic and racial groups having distinct genetic architectures that can
lead to differing genetic susceptibility. However, while studies like Encode and Gtex have mapped some of the
regulatory architecture of the human genome, they lack information on diverse populations, as these regulatory
mapping studies have also been almost exclusively in NHW, and not necessarily in the actual cell types that are
affected in Alzheimer disease (AD). This proposal will use multiple avenues of investigation to map the regulatory
architecture of the African and Amerindian Genomes, which, together with European, are the
components that contribute to the admixed AA and HI genomes. Once we have this architecture mapped, we
will use it to understand the mechanisms of disease associated with rare variants and associated non-coding
loci identified in AA and HI association studies. To accomplish this, we will use inducible pluripotent stem cells
from AA and HI (Peruvian) AD cases, chosen to maximize either African or Amerindian global ancestries, as well
as brain tissue from AA and HI individuals. With our collaborator Dr. Fulai Jin at Case Western Reserve
University, state of the art Hi-C techniques will be used to map interactions in both the differentiated iPSC lines
(neurons, oligodendrocytes, astrocytes and microglia) as well as the frozen brain tissue. We will also use single
nuclei RNAseq and single nuclei ATACseq to evaluate the brains, bulk ATAC and RNAseq for iPSC lines. All
the genomic data will then be complied, along with supporting existing data from European genomes (NHW), to
create the African and Amerindian regulatory maps. We will then take the identified associated haplotypes from
the outside AA and HI GWAS and rare variant studies and “lay” them across our regulatory
landscape to identify the interacting genes and subregions of the haplotypes affecting the risk for AD in these
populations. Next we will use CRISPRa and CRISPRi techniques to verify these interactions. Finally, we will
incorporate all this data with existing data to help identify high quality genetic targets for therapeutic intervention
for AD.

## Key facts

- **NIH application ID:** 10872131
- **Project number:** 5U01AG072579-04
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Derek Michael Dykxhoorn
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,381,687
- **Award type:** 5
- **Project period:** 2021-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872131

## Citation

> US National Institutes of Health, RePORTER application 10872131, Functional genomic studies in diverse populations to characterize risk loci for Alzheimer Disease (5U01AG072579-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10872131. Licensed CC0.

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