# Novel approaches to identify tandem repeat expansions in neurodegenerative disease

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $388,750

## Abstract

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases and has a high global
health burden. While several AD genetic risk loci have been identified, the causal variant at these genome-
wide association study (GWAS) sites is still unknown despite intensive sequencing efforts. Importantly,
however, most genome-wide sequencing methods fail to accurately resolve tandem repeats, over 40 of
which are key drivers of neurological disorders. We hypothesize that a substantial fraction of genetic
contributions to AD come from variable number tandem repeats (VNTRs) that often contain internal repeat
units 20 nucleotides or more and that until now have not been systematically assessed genome-wide. We
have surmounted critical sequencing barriers by establishing state-of-the-art long-read sequencing
techniques to amplify and characterize the exact nucleotide sequence across tandem repeats. We recently
reported the identification of a tandem repeat in WDR7 that is associated with Amyotrophic Lateral
Sclerosis (ALS). Using the pipeline that we established for tandem repeat length estimation and validation,
we propose to characterize human-specific tandem repeat expansions in AD. Our exciting preliminary
analysis reveals many examples of repeats with increased or decreased length in AD. Several of these
significantly differentially expanded repeats are in GWAS loci previously implicated in AD. Remarkably,
the lead SNP at these loci is associated with stepwise changes in repeat length in individuals heterozygous
or homozygous for the risk allele, suggesting that VNTRs may even play a causal role at these loci. We
also identify rare instances of massive expansions, and/or internal sequence differences that depend on
disease state. Our goal is to assess tandem repeats prone to expansion to estimate VNTR length genome-
wide in AD to identify the contribution of novel repeat expansions in disease. We leverage large cohorts of
whole genome sequence data from the Alzheimer’s Disease Sequencing Project. The thousands of
genomes available means we can detect VNTR expansions in Hispanic, African American and Non-
Hispanic White individuals as well as sex-specific effects of VNTR expansions. We will then perform
targeted long-read sequencing of AD DNA samples to resolve the complete sequence of tandem repeats
and define the consequence of internal sequence variation to AD. Finally, we will work to establish
mechanisms of pathogenesis of novel tandem repeat expansions in AD. Our proposed studies will
establish a novel paradigm to interrogate the mechanism of repeat expansion and will reveal insight into
novel genetic factors that cause or modulate risk for AD.

## Key facts

- **NIH application ID:** 10440935
- **Project number:** 1R01NS122766-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Paul Nils Valdmanis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $388,750
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440935

## Citation

> US National Institutes of Health, RePORTER application 10440935, Novel approaches to identify tandem repeat expansions in neurodegenerative disease (1R01NS122766-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10440935. Licensed CC0.

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