# Rare Variant Whole Genome Analysis and iPSC Validation of Putative Genetic Modifiers of Huntington Disease

> **NIH NIH R37** · J. DAVID GLADSTONE INSTITUTES · 2022 · $643,796

## Abstract

PROJECT SUMMARY
The goal of our studies is to identify and validate genes, proteins, and biological pathways that modulate
neurodegeneration induced by mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD). This
knowledge will provide new insights into the underlying mechanisms of HD and may reveal novel therapeutic
targets that are more druggable than mHtt. While mHtt is the major cause for HD, a number of studies have
indicated that genetic modifiers interact with mHtt to affect progression of neurodegeneration in HD. In fact, a
substantial genetic contribution to HD is not accounted for solely by the gene that encodes mHtt, or by the few
modifiers that have been identified by other research groups. We hypothesize that rare genetic variants
contribute to the disease onset and progression of HD that have been missed by genome-wide association
studies (GWAS) or candidate-based approaches. With this in mind, we conducted whole-genome sequencing
(WGS) on multiple HD families and identified candidates in novel genes not previously implicated in HD. They
are involved in protein clearance and other cellular pathways that may contribute to neurodegeneration in HD.
We provide direct evidence, for the first time, that a subset of these candidates modify neurodegeneration of
human striatal-like HD iPSC-derived neurons (HD striatal i-neuron).
 In the proposed studies, we will further validate and investigate the mechanisms by which these potential
genetic modifiers modulate neurodegeneration and expand our analysis to additional variants and their cellular
pathways that contribute to neurodegeneration in HD. Human neuron models recapitulate several key features
of HD, and a form of cellular imaging called robotic microscopy (RM) enables high-throughput (HT), high-content,
longitudinal single-neuron analysis of these models. The data sets generated by RM reveal different aspects of
neurodegeneration, including survival, analyzed by powerful statistical methods, or changes in neurite length,
which is a predictor of cellular stress. Our toolbox uses other powerful approaches to assess a candidates' effects
on neurodegeneration, such as an optical-pulse labeling (OPL) technology that can measure the rate of
clearance of proteins by proteasome activity or autophagy within single cells. We have an NIH X01 grant that is
sequencing 104 additional members of 19 new HD families for which we have extensive medical records and
clinical history on. We will extend our WGS analysis to these families and combine the data to identify a more
complete set of interacting gene partners and pathways and to help focus our list of current candidates that
contribute to HD onset and trajectory. New putative variants will be tested in our human HD i-neuron model to
validate them as potential genetic modifiers and to better define cellular pathways involved in modulating onset
of HD. The discovery of novel genetic modifiers of HD will further elucidate the disea...

## Key facts

- **NIH application ID:** 10415229
- **Project number:** 5R37NS101996-06
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** STEVEN M FINKBEINER
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $643,796
- **Award type:** 5
- **Project period:** 2017-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415229

## Citation

> US National Institutes of Health, RePORTER application 10415229, Rare Variant Whole Genome Analysis and iPSC Validation of Putative Genetic Modifiers of Huntington Disease (5R37NS101996-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10415229. Licensed CC0.

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