Genetic Variants Associated With Neurodegenerative Disorders in Patients With Amyotrophic Lateral Sclerosis and...

Area of Science:

• Neurogenetics
• Genomics
• Neurodegenerative Diseases

Background:

• Amyotrophic lateral sclerosis (ALS) exhibits significant clinical heterogeneity.
• The genetic underpinnings of this heterogeneity, particularly the role of genes implicated in other neurodegenerative disorders, are not well understood.
• Investigating rare variants in a broader spectrum of neurodegeneration-associated genes is crucial for a comprehensive understanding of ALS genetics.

Purpose of the Study:

• To investigate the association between rare variants in neurodegeneration-associated genes and the risk of developing amyotrophic lateral sclerosis (ALS).
• To determine if these rare variants influence the clinical phenotype, including motor function, cognitive status, and survival in ALS patients.
• To explore the concept of genetic pleiotropy across different neurodegenerative conditions.

Main Methods:

• A case-control study design was employed, including ALS patients lacking pathogenic variants in major ALS genes and matched controls.
• Whole-genome sequencing was utilized to identify high-impact rare variants (MAF <0.01% or novel) in 151 neurodegeneration-associated genes.
• Findings were validated using the large-scale Project MinE dataset, assessing ALS risk, motor phenotype, cognitive status, and survival.

Main Results:

• ALS patients carrying rare variants in neurodegeneration-associated genes were more frequent than in controls (16.1% vs 12.2%), indicating increased ALS risk (OR 1.37).
• Novel variants in Parkinson disease-associated genes (OR 3.62) and hereditary neuropathy genes (OR 3.30) significantly elevated ALS risk.
• Variant carriers exhibited a higher likelihood of the flail arm phenotype, increased risk of frontotemporal dementia, and reduced survival.

Conclusions:

• Rare variants in genes linked to other neurodegenerative disorders significantly impact both ALS susceptibility and clinical characteristics.
• This highlights genetic pleiotropy, suggesting a shared genetic architecture underlying various neurodegenerative diseases.
• Findings support a complex genetic model for ALS, involving shared variants that modulate disease expression, warranting cautious consideration for expanded genetic screening.