Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis
Abstract
Background Genetic studies have shown that C9orf72, SOD1, TARDBP and FUS are the most common mutated genes in amyotrophic lateral sclerosis (ALS). Here, we performed a meta-analysis to determine the mutation frequencies of these major ALS-related genes in patients with ALS. Methods We performed an extensive literature research to identify all original articles reporting frequencies of C9orf72, SOD1, TARDBP and FUS mutations in ALS. The mutation frequency and effect size of each study were combined. Possible sources of heterogeneity across studies were determined by meta-regression, sensitivity analysis and subgroup analysis. Results 111 studies were included in the meta-analysis. The overall pooled mutation frequencies of these major ALS-related genes were 47.7% in familial amyotrophic lateral sclerosis (FALS) and 5.2% in sporadic ALS (SALS). A significant difference was identified regarding the frequencies of mutations in major ALS genes between European and Asian patients. In European populations, the most common mutations were the C9orf72 repeat expansions (FALS 33.7%, SALS 5.1%), followed by SOD1 (FALS 14.8%, SALS 1.2%), TARDBP (FALS 4.2%, SALS 0.8%) and FUS mutations (FALS 2.8%, SALS 0.3%), while in Asian populations the most common mutations were SOD1 mutations (FALS 30.0%, SALS 1.5%), followed by FUS (FALS 6.4%, SALS 0.9%), C9orf72 (FALS 2.3%, SALS 0.3%) and TARDBP (FALS 1.5%, SALS 0.2%) mutations. Conclusions These findings demonstrated that the genetic architecture of ALS in Asian populations is distinct from that in European populations, which need to be given appropriate consideration when performing genetic testing of patients with ALS.
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The most common monogenic mutation linked with ALS, especially in populations of European ancestry, is the repeat expansion of the GGGGCC hexanucleotide in the first intron of the C9orf72 gene.
“The most common monogenic mutation linked with ALS, especially in populations of European ancestry, is the repeat expansion of the GGGGCC hexanucleotide in the first intron of the C9orf72 gene [5].”
From Lifestyle and medical conditions in relation to ALS risk and progression—an introduction to the Swedish ALSrisc Study (2024) · cites this paper as [5]
Mutations in SOD1 represent the second most common cause of familial ALS in Europeans and the most common cause in those of Asian descent.
“Mutations in the SOD1 gene, which encode the free radical/reactive oxygen species scavenger superoxide dismutase 1 [294,295], represent the second most common cause of familial ALS in Europeans and the most common cause in those of Asian descent [296].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [296]
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“common cause in those of Asian descent [296].”
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“The most common monogenic mutation linked with ALS, especially in populations of European ancestry, is the repeat expansion of the GGG GCC hexanucleotide in the first intron of the C9orf72 gene [5].”
Background
- Authors
- Zou, Z.-Y., Zhou, Z.-R., Che, C.-H., Liu, C.-Y., He, R.-L., & Huang, H.-P.
- Affiliations
- Union Hospital (CN)
- Shanghai Medical College of Fudan University (CN)
- Corresponding author
- Zou, Zhang-Yu
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2017-01-05
- Volume
- 88
- Issue
- 7
- Pages
- 540-549
- ISSN
- 0022-3050 (ISSN-L)
- 1468-330X
- OpenAlex
- W2569961244
- Cited by
- 540
- References
- 43
- Citations by year
- 2026: 37 · 2025: 67 · 2024: 80 · 2023: 77 · 2022: 87 · 2021: 64 · 2020: 72 · 2019: 24 · 2018: 27 · 2017: 5
- FWCI
- 4.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Natural Science Foundation of China
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, C9orf72, SOD1, TARDBP, FUS, mutation frequency, familial ALS, sporadic ALS, C9orf72 repeat expansion, genetic architecture, Asian populations, European populations, genetic testing
- MeSH terms
- Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Humans, Mutation, Molecular Epidemiology, Genetic Predisposition to Disease, White People, Asian People
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