# Identification and Characterization of ALS/FTD Associated Variants Using Whole Genome Sequencing

> **NIH NIH R56** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $586,250

## Abstract

Project Summary/Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by the selective loss
of motor neurons. It is ultimately lethal with a typical patient survival of two to five years. Symptoms of
frontotemporal dementia (FTD) can be detected in up to 50% of ALS patients and it is generally accepted the
ALS and FTD represent a continuum of disease (ALS/FTD). Although the etiology of a vast majority of
ALS/FTD cases is largely unknown, rare genetic factors likely play a major role in susceptibility to the disease.
Until recently, genetic studies have utilized data derived from exome sequencing due to the prohibitive cost of
whole genome sequencing (WGS) limiting analysis to coding regions of the genome. Variants within non-
coding genetic elements have been increasingly shown to be of vital importance in cellular regulation and
human disease. Such non-coding genetic elements include miRNAs, lncRNAs, and enhancers/silencers of
gene expression. However, dramatic reductions in the cost of whole genome sequencing now allow for the
screening of case:control cohorts for rare variants at a genome-wide scale. Furthermore, the identification of
structural variants, such as copy number variants, insertions, deletions and large rearrangements are
overcome through the use of WGS allowing for association studies for these elements with ALS/FTD. Through
our own efforts and the contributions of collaborators, we have amassed raw WGS data from over 5,000
ALS/FTD cases. Further, this cohort is expected to double in size to over 10,000 ALS/FTD cases within the
next 3 years. Here, we propose to identify and characterize novel genetic variants associated with ALS/FTD.
The Specific Aims of this proposal are: (1) Discovery of Candidate Genetic Variants Associated with
ALS/FTD. Raw WGS from our ALS/FTD cohort will be combined with raw WGS data generated from the
NHLBI’s TOPMed project representing up to 120,000 controls. After QC, variants (single nucleotide, indels and
other structural variants) will be identified and subject to numerous case:control analyses to identify novel
candidate variants associated with ALS/FTD. (2) Validation / Characterization of Novel Variants
Associated with ALS/FTD. Top candidate genetic variants will be replicated in an independent replication
cohort of an additional ~10,000 ALS/FTD cases through the Project MinE consortium. Validated elements will
be evaluated by several algorithms/databases to predict their potential functional impact and prioritized based
on their predicted functional impact to determine those that will be subject to functional analyses. (3)
Functional Analysis of Novel Variants Associated with ALS/FTD. Variants associated with ALS/FTD will be
evaluated in isogenic iPSC-derived motor neurons (iMNs) and murine models through several functional
analyses. These include survival/axon outgrowth by longitudinal imaging, axonal transport, nuclearcytoplasmic
transport, DNA damage, a...

## Key facts

- **NIH application ID:** 10216070
- **Project number:** 2R56NS073873-10
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** JOHN E LANDERS
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $586,250
- **Award type:** 2
- **Project period:** 2011-07-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216070

## Citation

> US National Institutes of Health, RePORTER application 10216070, Identification and Characterization of ALS/FTD Associated Variants Using Whole Genome Sequencing (2R56NS073873-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10216070. Licensed CC0.

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