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Sporadic ALS Risk Appears to Overlap Slightly With Other Neurodegenerative Conditions

NEW YORK (GenomeWeb) – A new study suggests some genetic overlap exists between amyotrophic lateral sclerosis (ALS) and at least two other neurodegenerative conditions: frontotemporal dementia and progressive supranuclear palsy.

"[W]e found that ALS is closely related genetically to frontotemporal dementia, but not to any of the other common neurodegenerative diseases, like Alzheimer's or Parkinson's," senior author Rahul Desikan, a radiology and biomedical imaging researcher at the University of California, San Francisco, said in a statement.

As they reported online today in JAMA Neurology, Desikan and colleagues looked for potential overlap between common variants implicated in ALS and those associated not only with frontotemporal dementia, but also with neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, corticobasal degeneration, and progressive supranuclear palsy.

Based on data for nearly 125,000 individuals with or without these conditions, the team tracked down SNPs in and around the C9orf72 and UNC13A genes that were linked to the risk of both ALS and FTD, along with a shared variant near the UNC13 gene. Another common variant overlapped between ALS and progressive supranuclear palsy, marking a haplotype near the NSF gene.

"[O]ur findings suggest that sporadic ALS may represent a polygenic disorder characterized by numerous genetic variants, each of which has a small association with disease risk," the authors wrote. "Although no single common variant may be informative clinically, the additive combination of risk variants may help identify individuals who are at greatest genetic risk for ALS."

The team — which included representatives from the International Frontotemporal Dementia-Genomics Consortium, the International Collaboration for Frontotemporal Dementia, the Progressive Supranuclear Palsy Genetics Consortium, and the International Parkinson's Disease Genomics Consortium — brought together summary statistics for 124,876 individuals included in prior genome-wide association studies.

Along with the variants that overlapped between ALS and frontotemporal dementia or between ALS and progressive supranuclear palsy, the researchers were able to narrow in on previously unappreciated associations for ALS.

For example, an ALS- and frontotemporal dementia-associated SNP near ERGIC1 appeared to influence brain- and spinal cord motor neuron expression of the BNIP1 gene — a notion supported by testing on central nervous system tissue samples from individuals with ALS, frontotemporal dementia, or progressive supranuclear palsy, or by experiments done using transgenic mouse models. 

"Additional work will be required to understand the role that tau plays in ALS and the relationship between BNIP1, mitophagy, and neurodegenerative diseases," Desikan and colleagues concluded. They cautioned that the current findings are based on data for individuals of European ancestry, which may lead to potential biases related to genetic architecture specific to Europeans.