TREM2 Variant p.R47H as a Risk Factor for Sporadic Amyotrophic Lateral Sclerosis
Open accessAbstract
IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which microglia play a significant and active role. Recently, a rare missense variant (p.R47H) in the microglial activating gene TREM2 was found to increase the risk of several neurodegenerative diseases, including Alzheimer disease. Whether the p.R47H variant is a risk factor for ALS is not known. OBJECTIVES: To determine whether p.R47H (rs75932628) in TREM2 is a risk factor for ALS and assess whether TREM2 expression is dysregulated in disease. DESIGN, SETTING, AND PARTICIPANTS: Samples of DNA from 923 individuals with sporadic ALS and 1854 healthy control individuals self-reported as non-Hispanic white were collected from ALS clinics in the United States and genotyped for the p.R47H variant in TREM2. Clinical data were obtained on ALS participants for genotype/phenotype correlations. Expression of TREM2 was measured by quantitative polymerase chain reaction and compared in spinal cord samples from 18 autopsied patients with ALS and 12 neurologically healthy controls, as well as from wild-type and transgenic SOD1G93A mice. MAIN OUTCOMES AND MEASURES: Minor allele frequency of rs75932628 and relative expression of TREM2. RESULTS: The TREM2 variant p.R47H was more common in patients with ALS than in the controls and is therefore a significant risk factor for ALS (odds ratio, 2.40; 95% CI, 1.29-4.15; P = 4.1×10-3). Furthermore, TREM2 expression was increased in spinal cord samples from ALS patients and SOD1G93A mice (P = 2.8×10-4 and P = 2.8×10-9, respectively), confirming dysregulated TREM2 in disease. Expression of TREM2 in the human spinal cord was negatively correlated with survival (P = .04) but not with other phenotypic aspects of disease. CONCLUSIONS AND RELEVANCE: This study demonstrates that the TREM2 p.R47H variant is a potent risk factor for sporadic ALS. To our knowledge, these findings identify the first genetic influence on neuroinflammation in ALS and highlight the TREM2 signaling pathway as a therapeutic target in ALS and other neurodegenerative diseases.
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The Alzheimer disease-associated R47H variant of TREM2, which impairs microglial activation, survival, and proliferation, is also a risk factor for sporadic amyotrophic lateral sclerosis.
“the AD-associated R47H variant of TREM2, which impairs microglial activation, survival, and proliferation, was also found to be a risk factor for sporadic ALS (155).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [155]
Loss of function mutations in TREM2 are risk factors for ALS.
“loss of function mutations in TREM2 (triggering receptor expressed on myeloid cells 2), which affect microglia phagocytosis and inflammation, are risk factors for ALS [425–427]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [425]
Microglia play a pivotal role in ALS pathogenesis.
“confirming the pivotal role played by microglia in ALS pathogenesis.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [425]
The R47H variant was found to be associated with frontotemporal dementia, Parkinson's disease and amyotrophic lateral sclerosis.
“Furthermore, the R47H variant was investigated in other neurodegenerative diseases and was also found to be associated with frontotemporal dementia, Parkinson’s disease and amyotrophic lateral sclerosis (23,24), suggesting a more widespread role for TREM2 in maintaining microglial function/survival throughout the brain.”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [23]
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Diaz-Lucena, D., Kruse, N., Thüne, K., Schmitz, M., Villar-Piqué, A., da Cunha, J. E. G., Hermann, P., López-Pérez, Ó., Andrés-Benito, P., Ladogana, A., et al. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02296-1 · Cited by 32 · see citing works
Varnum, M. M., Clayton, K. A., Yoshii-Kitahara, A., Yonemoto, G., Koro, L., Ikezu, S., & Ikezu, T. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.759159 · Cited by 22 · see citing works
TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo
Lee-Gosselin, A., Jury-Garfe, N., You, Y., Dabin, L., Soni, D., Dutta, S., Rochet, J.-C., Kim, J., Oblak, A. L., & Lasagna-Reeves, C. A. (2023) · Cells · doi:10.3390/cells12121597 · Cited by 19 · see citing works
Sánchez‐Ruiz de Gordoa, J., Erro, M. E., Vicuña‐Urriza, J., Zelaya, M. V., Tellechea, P., Acha, B., Zueco, S., Urdánoz‐Casado, A., Roldán, M., Blanco‐Luquin, I., et al. (2020) · Movement Disorders · doi:10.1002/mds.27992 · Cited by 18 · see citing works
- Authors
- Cady, J., Koval, E. D., Benitez, B. A., Zaidman, C., Jockel-Balsarotti, J., Allred, P., Baloh, R. H., Ravits, J., Simpson, E., Appel, S. H., Pestronk, A., Goate, A. M., Miller, T. M., Cruchaga, C., & Harms, M. B.
- Affiliations
- Washington University in St. Louis (US)
- Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri
- Department of Neurology, Washington University School of Medicine, St Louis, Missouri
- Cedars-Sinai Medical Center (US)
- University of California San Diego (US)
- Houston Methodist (US)
- Corresponding author
- Harms, Matthew B.
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2014-04-01
- Volume
- 71
- Issue
- 4
- Pages
- 449
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC4087113
- OpenAlex
- W2064941321
- Cited by
- 262
- References
- 22
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 12 · 2023: 16 · 2022: 13 · 2021: 21 · 2020: 16 · 2019: 22 · 2018: 26 · 2017: 31 · 2016: 23 · 2015: 34 · 2014: 17
- FWCI
- 22.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1rc2hl103010-01, UL1TR000448)
- National Institute on Aging (RF1AG044546, R01AG044546)
- National Heart, Lung, and Blood Institute (HL 102923, RC2HL102925, HL-102924, HL-102925, RC2HL102926, RC2HL102923, T32HL083822, UC2HL102924, RC2HL-103010, UC2HL102925, HL 103010, UC2HL102923, UC2HL103010, RC2HL102924, UC2HL102926, 5-T32-HL-83822-5)
- National Institute of Neurological Disorders and Stroke (R01NS069669, K08NS075094, R01-NS078398-02, R01NS078398)
- National Center for Research Resources (UL1RR024992)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- amyotrophic lateral sclerosis, TREM2, genetic risk factors, microglia, neuroinflammation, SOD1 G93A mice, survival, spinal cord, neurodegeneration, therapeutic target, genotype-phenotype correlation
- MeSH terms
- Superoxide Dismutase-1, Adult, Aged, Amyotrophic Lateral Sclerosis, Animals, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Inflammation, Male, Membrane Glycoproteins, Mice, Transgenic, Middle Aged, Phenotype, Receptors, Immunologic, Risk Factors, Superoxide Dismutase, Genetic Variation, Cohort Studies, Signal Transduction, Case-Control Studies, Microglia, Genetic Predisposition to Disease, Mice
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