# Rare Genetic Risk and Gene Networks in Tauopathy

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $177,444

## Abstract

Project Summary
Neurodegenerative diseases associated with aging are clinically and pathologically defined syndromes with
heterogeneous genetic endophenotypes, some of which are unique to one disease while others are shared
across diseases. Despite the economic and healthcare burden, treatments targeted to endophenotypes are not
available for neurodegenerative tauopathies such as Alzheimer’s disease (AD) and Progressive Supranuclear
Palsy (PSP). AD and PSP are pathologically related by abnormal tau protein inclusions and the tau gene is a
shared genetic risk factor. Unique genetic risk in common variants have been identified for AD (ABCA7, BIN1)
and PSP (STX6, EIF2AK3). However, a significant part of genetic heritability remains unexplained; a proportion
of which is likely due to rare variants. Identification of rare genetic risk factors may delineate the endophenotypes
of AD and PSP, unlocking future therapeutic targets. The objectives of this proposal are to identify and validate
rare genetic risk factors that are unique to or shared by AD and PSP. The long-term goal is to realize precision
medicine for neurodegenerative dementias by leveraging genomics and biomedical informatics. Traditional rare
variant analyses have limited power due to the large number of variants and small variant effect size. Although
one solution is to group variants into genes, genes do not act in isolation, but rather interact with one another in
networks. Grouping variants in a network can improve power. Additionally, since most genetic risk lies in large
noncoding regions of the genome, focusing analyses on noncoding regulatory regions should further increase
power. We hypothesize that incorporating network connectivity in rare variant statistical tests and prioritizing
functional noncoding variants followed by validation will identify rare genetic risk factors in AD and PSP by
overcoming deficiencies in traditional methods. To test this hypothesis, we propose the following aims. Aim 1 is
to develop and apply rare variant statistical tests that incorporate network connectivity to identify dementia risk
genes. Aim 2 is to identify noncoding rare genetic risk variants by developing a noncoding prioritization and gene
assignment strategy. Aim 3 is to validate rare variants that are unique to or shared by AD and PSP. The advances
from these studies will expand our understanding of dementia risk and provide new targets for therapeutic
development in neurodegenerative disease. The K08 training will build on my previous strengths in clinical
informatics to gain expertise in genetics, genome informatics and functional genomics. My mentorship team will
consist of faculty with expertise in these domains and clinical care. We will have regular meetings and monitor
progress. The environment at UCLA includes interdepartmental collaborations, powerful computing resources,
and genetic laboratory resources to complete the aims. The career development plan forges a pathway to
become ...

## Key facts

- **NIH application ID:** 10841011
- **Project number:** 5K08AG065519-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Timothy S Chang
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $177,444
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841011

## Citation

> US National Institutes of Health, RePORTER application 10841011, Rare Genetic Risk and Gene Networks in Tauopathy (5K08AG065519-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10841011. Licensed CC0.

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