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, and global gene expression/splicing patterns. These studies will further our understanding of the impact of the variant towards ALS/FTD pathogenesis.

Public Health Relevance

Amyotrophic lateral sclerosis and frontotemporal dementia (ALS) represent a continuum of disease (ALS/FTD). The etiology of a vast majority of ALS/FTD cases is largely unknown restricted until recently by the high cost of whole genome sequencing. Here, we propose to identify and characterize genetic factors contributing to ALS/FTD using whole genome sequencing data furthering our understanding of disease pathogenesis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1)
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Gubitz, Amelie
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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