Complex genetic interactions in ALS affecting neuron health and disease onset.

Decoding ALS: How Genetic Variants Accelerate Disease Onset

Beau Callahan in Health & Wellness June 2025 • 4 min read.

"New research reveals how multiple rare genetic variants can significantly impact the age of onset for Amyotrophic Lateral Sclerosis (ALS), offering potential new avenues for treatment and understanding."

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons. This leads to muscle weakness, paralysis, and ultimately, respiratory failure. While 5-10% of ALS cases are familial (FALS), the majority are sporadic (SALS), making the search for the underlying causes particularly challenging.

Recent advances in genetic research have identified over 20 genes associated with FALS. However, the genetic basis of SALS remains less clear, prompting scientists to explore more complex genetic interactions. A prevailing hypothesis suggests that a combination of multiple rare variants in ALS-related genes may contribute to disease onset and progression.

Now, a recent study published in the Journal of Neurology, Neurosurgery & Psychiatry sheds light on this hypothesis, demonstrating how the burden of rare genetic variants in causative genes can accelerate the age of ALS onset in a Japanese population. This research highlights the intricate interplay between genetic factors and the variable nature of ALS.

Unraveling the Genetic Puzzle: Key Findings on ALS Onset

Complex genetic interactions in ALS affecting neuron health and disease onset.

The study, led by researchers from the University of Tokyo and other Japanese institutions, involved whole-exome sequencing analysis of 89 families with FALS and 410 patients with SALS. The goal was to identify known pathogenic mutations and rare, functionally predicted deleterious variants in genes known to cause ALS. Rare variants were defined as those with a minor allele frequency of less than 1% and a scaled Combined Annotation-Dependent Depletion (CADD) score greater than 20.

The analysis revealed that a significant proportion of patients carried either known pathogenic mutations or rare deleterious variants in ALS-related genes: 62.9% of FALS families and 21.2% of SALS patients. Notably, some individuals carried variants in multiple genes, leading to a crucial observation.

Accelerated Onset: Patients with multiple variants experienced a significantly earlier onset of ALS compared to those with only one or no variants.
Independent Effect: Even when excluding patients with known pathogenic mutations, the presence of multiple rare deleterious variants still correlated with an earlier disease onset.
Statistical Significance: Multiple regression analysis confirmed that the number of variants and a family history of ALS were significantly associated with the age of onset.

These findings suggest that the cumulative effect of multiple rare variants in ALS-related genes can act as a significant driver of disease onset, even in the absence of established pathogenic mutations. This points towards a more complex, oligogenic model of ALS, where multiple genes interact to influence disease susceptibility and progression.

Implications and Future Directions

This study provides compelling evidence that the burden of rare variants in ALS-related genes plays a crucial role in determining the age of disease onset. These results highlight the need for comprehensive genetic analyses in ALS patients to identify not only known pathogenic mutations but also the presence of multiple rare variants. Understanding these complex genetic interactions could pave the way for personalized therapeutic strategies that target specific genetic profiles.

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This article is based on research published under:

DOI-LINK: 10.1136/jnnp-2018-318568, Alternate LINK

Title: Burden Of Rare Variants In Causative Genes For Amyotrophic Lateral Sclerosis (Als) Accelerates Age At Onset Of Als

Subject: Psychiatry and Mental health

Journal: Journal of Neurology, Neurosurgery & Psychiatry

Publisher: BMJ

Authors: Hiroya Naruse, Hiroyuki Ishiura, Jun Mitsui, Yuji Takahashi, Takashi Matsukawa, Masaki Tanaka, Koichiro Doi, Jun Yoshimura, Shinichi Morishita, Jun Goto, Tatsushi Toda, Shoji Tsuji

Published: 2018-10-24

Everything You Need To Know

What exactly is Amyotrophic Lateral Sclerosis (ALS)?

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that leads to the loss of motor neurons. As motor neurons degenerate, it causes muscle weakness and eventually paralysis and respiratory failure. ALS can be familial (FALS), meaning it runs in families, or sporadic (SALS), occurring in individuals with no known family history of the disease. Understanding the distinction between FALS and SALS is important for genetic research as it helps scientists understand the genetic and environmental factors that contribute to the disease.

Why are rare genetic variants important in the context of ALS?

Rare genetic variants, particularly in genes related to ALS, are significant because they can influence when the disease starts. A higher number of these variants in an individual correlates with an earlier onset of ALS. This suggests that the cumulative effect of multiple rare variants can act as a significant driver of disease onset, even in the absence of established pathogenic mutations. Identifying these variants is crucial for understanding the genetic complexity of ALS and developing personalized treatment strategies.

How did the researchers go about identifying the genetic variants that influence ALS?

The study used whole-exome sequencing to analyze the genomes of families with FALS and individuals with SALS. By identifying both known pathogenic mutations and rare deleterious variants in ALS-related genes, researchers aimed to understand how these genetic factors contribute to the onset and progression of the disease. This comprehensive genetic analysis helps to uncover the complex interplay between multiple genes and their impact on the variability observed in ALS.

How does having multiple rare variants affect when ALS symptoms start?

The presence of multiple rare variants in ALS-related genes can significantly accelerate the onset of the disease. Even when excluding patients with known pathogenic mutations, the presence of multiple rare deleterious variants still correlated with an earlier disease onset. This finding supports an oligogenic model of ALS, where multiple genes interact to influence disease susceptibility and progression, suggesting that the combined effect of these variants plays a critical role in determining when the disease manifests.

What do these discoveries mean for treating ALS in the future?

The discoveries highlight the importance of comprehensive genetic analyses in ALS patients to identify not only known pathogenic mutations but also the presence of multiple rare variants. Understanding these complex genetic interactions could pave the way for personalized therapeutic strategies that target specific genetic profiles, potentially leading to more effective treatments and improved outcomes for individuals affected by ALS. Future research may focus on developing therapies that counteract the effects of these rare variants or mitigate their impact on disease progression.