Genomics: Insight

Research Question: What is the influence of genes and environmental factors on the risk of developing ALS and the severity of its symptoms?

Introduction 

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, affects around 30,000 people, or around 9.1 per 100,000 U.S. population, with only about 50% living past 3 years after diagnosis, and only 25 % after 5 years.⁷ It is a progressive neurodegenerative disorder that affects motor neurons in the brain and spinal cord. Symptoms include muscle weakness, paralysis, and eventually respiratory failure and death. It primarily impacts voluntary movement, causing symptoms like muscle atrophy, twitching, and difficulty speaking or swallowing. There is no known cure for ALS, and current treatments only slightly slow its progression. Given its devastating effects and the gaps in understanding its causes, ALS remains a critical area of study. Furthermore, the specific societal significance is increasing. Approximately 10% of patients are considered to have fALS (familial ALS), marked by at least one other family member being afflicted by ALS as well. The rest of the ALS cases are considered sALS (sporadic ALS) due to not correlating with genetic history. In fALS, 45-55% of cases have been explained by variations in genes known to be linked to ALS. In sALS, the use of twin studies has attributed heritability, or the significance of genetic factors, to having about a 60% impact on the prevalence of the disease in nonfamilial-related cases.¹

Genomic Correlations and Significance

Genetic factors play an integral role in the presence of symptomatic ALS in the population. Studies have highlighted that mutations in the SOD1 and C9orf72 have a strong relation to the presence of ALS. Slightly less significant correlations have also been attributed to mutations of FUS and TARDBP genes. A data set in 2017 observes the relative prevalence of mutated genes in fALS patients and sALS patients of European and Asian descent. In fALS cases, the most commonly associated genes are SOD1 and C9orf72, with SOD1 mutations appearing more frequently in Asian fALS cases (30%) compared to European fALS cases (14.8%).¹ Conversely, C9orf72 mutations are significantly more common in European fALS cases (33.7%) compared to Asian fALS cases (2.3%).¹ In sALS cases, the vast majority of cases remain unexplained by known genetic mutations, with 92.6% of European sALS and 97.1% of Asian sALS classified as "Other/Unknown."¹ In cases of sALS, the known ALS-linked genes (SOD1, C9orf72, TARDBP, and FUS) account for a much smaller percentage, indicating that other genetic and/or environmental factors may also play a role in its development. This data set highlights a significant genetic component in fALS, while sALS remains largely unexplained genetically, reinforcing the importance of continued genetic research in ALS pathogenesis. In contrast, a 2021 study examined the prevalence and incidence of ALS across different geographic regions and evaluated the association of ALS with SOD1 and C9orf72 genetic variations. While SOD1 and C9orf72 mutations are more commonly associated with fALS, this study directly contradicts the previous data set, suggesting a correlation between sALS and genetic factors by depicting that the same genetic variants also appear in sALS cases. The study pooled data on ALS cases per 100,000 persons and analyzed the estimated number of prevalent and incident cases for SOD1 and C9orf72 genetic variants.² The total estimated number of prevalent SOD1 cases is 2,876, with 1,342 (47%) of these cases occurring in fALS and 1,534 (53%) in sALS.² Similarly, for incident SOD1 cases, there are 946 total, of which 434 (46%) are fALS and 512 (54%) are sALS.² These numbers suggest that SOD1 mutations, while traditionally linked to familial ALS, are also found in a significant percentage of sporadic ALS cases. This aligns with the growing evidence that sALS may have a genetic component that remains largely unexplored. Likewise, for the C9orf72 gene, the total number of prevalent cases is 4,545, of which 1,198 (26%) are fALS and 3,347 (74%) are sALS.² Similarly, for incident C9orf72 cases, there are 1,706 cases, with 450 (26%) occurring in fALS and 1,256 (74%) in sALS.² The high proportion of C9orf72 mutations in sALS cases may indicate unknown heritability factors; however, since no known family members with ALS are present within two generations in sALS cases, the proportion more likely supports the notion that sporadic ALS may have a genetic basis in some patients, even if they lack a clear familial history. Overall, these opposing data sets highlight the need for continued genetic research to understand the mechanisms underlying ALS fully and to develop targeted treatments based on genetic risk factors.

Environmental Factors - Military Service and Chemical Exposure

Although sALS is mostly unpredictable, studies have identified significant ties to exposure to heavy metals as one of the few identified environmental risk factors. The following data set from 2021 identifies the relation between exposure to certain chemicals/metals (BMAA, heavy metals, manganese, mercury, and zinc) through mean odds ratios as an environmental factor concerning the presentation of ALS. An odds ratio greater than one means a greater association with the exposure and outcome. The investigation put together 62 population exposure studies that implicated the same group of environmental agents (mean odds ratios): BMAA (2.32), formaldehyde (1.54), heavy metals (2.99), manganese (3.85), mercury (2.74), and zinc (2.78).⁴ This establishes BMAA, formaldehyde, heavy metals, manganese, mercury, and zinc as environmental factors closely tied to ALS, with manganese and heavy metals having the strongest association, and formaldehyde association being the weakest.
Though roughly 10% of ALS cases are young-onset, or diagnosed before age 45, expression and development of ALS are most commonly present in later years of life, with the associated symptoms negatively impacting one’s quality of life significantly. An article cites higher odds of ALS for veterans whose longest deployment was World War II or the Korean War (OR=1.27; 95% CI: 1.06, 1.52).³ Generally, there was found to be a positive trend relating to years deployed to ALS. ALS was positively associated with exposure to herbicides for military purposes, nasopharyngeal radium, personal pesticides, exhaust from heaters or generators, high-intensity radar waves, contaminated food, explosions within one mile, herbicides in the field, mixing and application of burning agents, burning agents in the field, and Agent Orange in the field, with ORs between 1.50 and 7.7.3  This data set suggests a correlation between military service, including exposure to the aforementioned chemicals, and presentation of ALS, identifying a significant at-risk social group. 
An additional study observed the connection between military service and exposure to heavy metals, with a total of 2642 articles screened. In general, the relationship between military service was suggestive of an increased risk, particularly among veterans who served in the Gulf War or WWII. Additionally, pesticides (including Agent Orange), certain chemicals (exhaust, burning agents), heavy metals, and head trauma appeared to increase the risk of ALS among military personnel.⁵ This further supports the connection between chemical exposure and the prevalence of ALS in military veterans. 
One review investigated the potential risk of amyotrophic lateral sclerosis (ALS) in competitive contact sports involving repetitive concussive head and/or cervical spinal trauma.⁶ This was achieved by contrasting incidence and mortality rates of ALS in athletes versus non-athletes, as well as these injuries and their risk for the disease with the general population or non-sport controls. Professional and nonprofessional athletes from a variety of sports, including basketball, American football, soccer, cycling, marathoning, skating, and other unidentified sports, were included in the sample of the systematic review, which examined 16 research articles. 
Professional sports involving recurrent concussive damage had a pooled rate ratio (RR) of 8.52 (95% CI 5.18-14.0), indicating a markedly elevated risk of ALS.⁶ A pooled rate ratio is a measure of the effect size in a meta-analysis. Comparatively, nonprofessional contact sports had a significantly lower pooled RR of 0.60 (95% CI 0.12-3.06). Similarly, nonprofessional non-contact sports had an RR of 1.17 (95% CI 0.79-1.71), whereas professional sports not prone to head trauma had an RR of 1.35 (95% CI 0.67-2.71).⁶ These results imply that exposure to repetitive concussive trauma and professional sports activity independently raises the risk of developing ALS. Professional-level sports and repeated concussive injuries increase this risk, suggesting mechanical trauma as an environmental trigger for ALS, particularly in genetically susceptible people, illustrating the myriad factors that can contribute to the presence of ALS in a patient. In the case of veterans, head trauma should be considered a significant risk factor and suggests a need for policies regulating military deployment to consider screening for mutations of the related genes to at least recognize this risk.

Conclusion 

ALS develops through a combination of genetic predisposition and environmental influences. While fALS is strongly linked to mutations in genes like SOD1 and C9orf72, these mutations are also found in many sALS cases, suggesting a broader significant hereditary component. Environmental factors such as exposure to heavy metals, pesticides, and repeated head trauma, particularly in military personnel and athletes, also significantly influence the risk of ALS in susceptible individuals. Therefore, the study of the interaction between genetic and environmental factors expands the possibility of improving early detection, developing targeted treatments, and identifying potential prevention strategies.

"ALS develops through a combination of genetic predisposition and environmental influences."

References

1. Zou, Z.-Y., Zhou, Z.-R., Che, C.-H., Liu, C.-Y., He, R.-L., and Huang, H.-P. (2017). Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J. Neurol. Neurosurg. Psychiatr. 88, 540–549.

2. Brown, Carolyn A et al. “Estimated Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1 and C9orf72 Genetic Variants.” Neuroepidemiology vol. 55,5 (2021): 342-353. doi:10.1159/000516752

3. Beard, John D et al. “Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology.” Environment International vol. 91 (2016): 104-15. doi:10.1016/j.envint.2016.02.014

4. Newell, Melanie Engstrom, et al. “Systematic and state-of-the-science review of the role of environmental factors in Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's Disease.” The Science of the Total Environment vol. 817 (2022): 152504. doi:10.1016/j.scitotenv.2021.152504

5. McKay, Kyla A et al. “Military service and related risk factors for amyotrophic lateral sclerosis.” Acta neurologica Scandinavica vol. 143,1 (2021): 39-50. doi:10.1111/ane.13345

6. Blecher, R., Elliott, M. A., Yilmaz, E., Dettori, J. R., Oskouian, R. J., Patel, A., Clarke, A., Hutton, M., McGuire, R., Dunn, R., DeVine, J., Twaddle, B., & Chapman, J. R. (2019). Contact Sports as a Risk Factor for Amyotrophic Lateral Sclerosis: A Systematic Review. Global Spine Journal. https://doi.org/10.1177/2192568218813916

7. Mehta, P., Raymond, J., Zhang, Y., Punjani, R., Han, M., Larson, T., … Horton, D. K. (2023). Prevalence of amyotrophic lateral sclerosis in the United States, 2018. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 24(7–8), 702–708. https://doi.org/10.1080/21678421.2023.2245858