Identification of a rare coding variant in TREM2 in a Chinese individual with Alzheimer’s disease
Open accessAbstract
Rare variation in the TREM2 gene is associated with a broad spectrum of neurodegenerative disorders including Alzheimer's disease (AD). TREM2 encodes a receptor expressed in microglia which is thought to influence neurodegeneration by sensing damage signals and regulating neuroinflammation. Many of the variants reported to be associated with AD, including the rare R47H variant, were discovered in populations of European ancestry and have not replicated in diverse populations from other genetic backgrounds. We utilized a cohort of elderly Chinese individuals diagnosed as cognitively normal, or with mild cognitive impairment or AD to identify a rare variant, A192T, present in a single patient diagnosed with AD. We characterized this variant using biochemical cell surface expression assays and found that it significantly altered cell surface expression of the TREM2 protein. Together these data provide evidence that the A192T variant in TREM2 could contribute risk for AD. This study underscores the increasingly recognized role of immune-related processes in AD and highlights the importance of including diverse populations in research to identify genetic variation that contributes risk for AD and other neurodegenerative disorders.
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To date, thousands of Chinese and Japanese have been screened for the TREM2 p.R47H variant, and only three Japanese carriers have been reported.
“To date, thousands of Chinese and Japanese have been screened for p.R47H variant, and only three Japanese carriers of this variant have been reported (Table 4) [38–42].”
From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [41]
The Introduction says the R47H finding had not been replicated in East Asian populations and cites Chinese and Japanese studies. It does not state that thousands of people were screened or that exactly three Japanese carriers were reported. No page number is available in our copy. (LLM, conf=0.77)
Experimental — accuracy not yet measuredGenetic studies in East Asian populations have been unable to replicate the significance of the TREM2 p.R47H variant because it is rarely found in this population.
“However, genetic studies in East Asian populations have been unable to replicate the significance of the p.R47H variant in TREM2, because it is rarely found in this population.”
From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [41]
The Introduction says the R47H finding had not been replicated in East Asian populations. It does not say that this is because R47H is rarely found there; the East Asian frequency reported in the Discussion concerns a different variant, A192T. (LLM, conf=0.87)
Experimental — accuracy not yet measured
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Cites
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · see citing works
TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
Kleinberger, G., Yamanishi, Y., Suárez-Calvet, M., Czirr, E., Lohmann, E., Cuyvers, E., Struyfs, H., Pettkus, N., Wenninger-Weinzierl, A., Mazaheri, F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009093 · Cited by 798 · see citing works
Patterns of cognitive and emotional empathy in frontotemporal lobar degeneration
Rankin, K. P., Kramer, J. H., & Miller, B. L. (2005) · Cognitive and Behavioral Neurology · doi:10.1097/01.wnn.0000152225.05377.ab · Cited by 343 · see citing works
Self-citationCoding variants in TREM2 increase risk for Alzheimer's disease
Jin, S. C., Benitez, B. A., Karch, C. M., Cooper, B., Skorupa, T., Carrell, D., Norton, J. B., Hsu, S., Harari, O., Cai, Y., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu277 · Cited by 314 · see citing works
TREM2 in CNS homeostasis and neurodegenerative disease
Painter, M. M., Atagi, Y., Liu, C.-C., Rademakers, R., Xu, H., Fryer, J. D., & Bu, G. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0040-9 · Cited by 169 · see citing works
Guerreiro, R., Bilgic, B., Guven, G., Brás, J., Rohrer, J., Lohmann, E., Hanagasi, H., Gurvit, H., & Emre, M. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.06.005 · Cited by 158 · see citing works
TREM2 is associated with increased risk for Alzheimer’s disease in African Americans
Jin, S. C., Carrasquillo, M. M., Benitez, B. A., Skorupa, T., Carrell, D., Patel, D., Lincoln, S., Krishnan, S., Kachadoorian, M., Reitz, C., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0016-9 · Cited by 153 · see citing works
A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese
Jiang, T., Tan, L., Chen, Q., Tan, M.-S., Zhou, J.-S., Zhu, X.-C., Lu, H., Wang, H.-F., Zhang, Y.-D., & Yu, J.-T. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.02.023 · Cited by 110 · see citing works
Flagged first, then by citations
Research works printed but not linked: 23
- Albert M DeKosky ST Dickson D Dubois B Feldman HH Fox N Phelps C 2011 The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease Alzheimer’s and Dementia 7 270 279 10.1016/j.jalz.2011.03.008 PMC3312027 21514249 · DOI · Paper page
- Borroni B Ferrari F Galimberti D Nacmias B Barone C Bagnoli S Padovani A 2014 Heterozygous TREM2 mutations in frontotemporal dementia Neurobiology of Aging 35 4 10.1016/j.neurobiolaging.2013.09.017 24139279 · DOI · Paper page
- Carson AR Smith EN Matsui H Brækkan SK Jepsen K Hansen J-B Frazer KA 2014 Effective filtering strategies to improve data quality from population-based whole exome sequencing studies BMC Bioinformatics 15 125 10.1186/1471-2105-15-125 24884706 PMC4098776 · DOI
- Chao SZ Lai NB Tse MM Ho RJ Kong JP Matthews BR Rosen HJ 2011 Recruitment of Chinese American elders into dementia research: The UCSF ADRC experience The Gerontologist 51 S125 33 10.1093/geront/gnr033 21565814 PMC3092979 · DOI
- Chao SZ Matthews BR Yokoyama JS Lai NB Ong H Tse M Rosen HJ 2014 Depressive symptoms in Chinese-American subjects with cognitive impairment American Journal of Geriatric Psychiatry 22 642 652 10.1016/j.jagp.2012.10.029 24021225 PMC4309267 · DOI
- Colonna M Wang Y 2016 TREM2 variants: New keys to decipher Alzheimer disease pathogenesis Nature Reviews. Neuroscience 17 201 207 10.1038/nrn.2016.7 26911435 · DOI · Paper page
- Folstein MF Folstein SE McHugh PR 1975 “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician Journal of Psychiatric Research 12 189 198 10.1016/0022-3956(75)90026-6 1202204 · DOI · Paper page
- Guerreiro R Wojtas A Bras J Carrasquillo M Rogaeva E Majounie E Hardy J 2013 TREM2 variants in Alzheimer’s disease The New England Journal of Medicine 368 117 127 10.1056/NEJMoa1211851 23150934 PMC3631573 · DOI · Paper page
- Huang M Wang D Xu Z Xu Y Xu X Ma Y Xia Z 2015 Lack of genetic association between TREM2 and Alzheimer’s disease in East Asian population: A systematic review and meta-analysis American Journal of Alzheimer’s Disease and Other Dementias 30 541 546 10.1177/1533317515577128 PMC10852690 25852195 · DOI · Paper page
- Jonsson T Stefansson H Steinberg S Jonsdottir I Jonsson PV Snaedal J Stefansson K 2013 Variant of TREM2 associated with the risk of Alzheimer’s disease The New England Journal of Medicine 368 107 116 10.1056/NEJMoa1211103 23150908 PMC3677583 · DOI · Paper page
- Kiialainen A Hovanes K Paloneva J Kopra O Peltonen L 2005 Dap12 and Trem2, molecules involved in innate immunity and neurodegeneration, are co-expressed in the CNS Neurobiology of Disease 18 314 322 10.1016/j.nbd.2004.09.007 15686960 · DOI · Paper page
- Lek M Karczewski K Minikel E Samocha K Banks E Fennell T MacArthur D 2016 Analysis of protein-coding genetic variation in 60,706 humans Nature 536 7616 285 291 JOUR. Retrieved from doi: http://dx.doi.org/10.1038/nature19057 27535533 PMC5018207 · DOI · Paper page
- Ma J Zhou Y Xu J Liu X Wang Y Deng Y Chen S 2014 Association study of TREM2 polymorphism rs75932628 with late-onset Alzheimer’s disease in Chinese Han population Neurological Research 36 894 896 10.1179/1743132814Y.0000000376 24725293 · DOI
- McKenna A Hanna M Banks E Sivachenko A Cibulskis K Kernytsky A DePristo MA 2010 The genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data Genome Research 20 1297 1303 10.1101/gr.107524.110 20644199 PMC2928508 · DOI · Paper page
- Mckhann G Knopman DS Chertkow H Hyman BT Jack CR Kawas C Phelps C 2011 The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease Alzheimer’s and Dementia 7 263 269 10.1016/j.jalz.2011.03.005 PMC3312024 21514250 · DOI · Paper page
- Miyashita A Wen Y Kitamura N Matsubara E Kawarabayashi T Shoji M Kuwano R 2014 Lack of Genetic Association between TREM2 and late-onset Alzheimer’s disease in a Japanese population Journal of Alzheimer’s Disease: JAD 41 1031 1038 10.3233/JAD-140225 24762945 · DOI · Paper page
- Park JS Ji IJ An HJ Kang MJ Kang SW Kim DH Yoon SY 2015 Disease-associated mutations of TREM2 alter the processing of N-linked oligosaccharides in the Golgi apparatus Traffic 16 510 518 10.1111/tra.12264 25615530 · DOI
- Possin KL Laluz VR Alcantar OZ Miller BL Kramer JH 2011 Distinct neuroanatomical substrates and cognitive mechanisms of figure copy performance in Alzheimer’s disease and behavioral variant frontotemporal dementia Neuropsychologia 49 43 48 10.1016/j.neuropsychologia.2010.10.026 21029744 PMC3005024 · DOI
- Purcell S Neale B Todd-Brown K Thomas L Ferreira MA Bender D Sham PC 2007 PLINK: A tool set for whole-genome association and population-based linkage analyses American Journal of Human Genetics 81 559 575 10.1086/519795 17701901 PMC1950838 · DOI · Paper page
- Wang Y Cella M Mallinson K Ulrich JD Young KL Robinette ML Colonna M 2015 TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model Cell 160 1061 1071 10.1016/j.cell.2015.01.049 25728668 PMC4477963 · DOI · Paper page
- Yokoyama JS Lee AKL Takada LT Busovaca E Bonham LW Chao SZ Rosen HJ 2015 Apolipoprotein ε4 is associated with lower brain volume in cognitively normal Chinese but not white older adults PLoS One 10 e0118338 10.1371/journal.pone.0118338 25738563 PMC4349764 · DOI
- Yu JT Jiang T Wang YL Wang HF Zhang W Hu N Tan L 2014 Triggering receptor expressed on myeloid cells 2 variant is rare in late-onset Alzheimer’s disease in Han Chinese individuals Neurobiology of Aging 35 937.e1 937.e3 10.1016/j.neurobiolaging.2013.10.075 24184202 · DOI · Paper page
- Yuan P Condello C Keene CD Wang Y Bird TD Paul SM Grutzendler J 2016 TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy Neuron 90 724 739 10.1016/j.neuron.2016.05.003 27196974 PMC4898967 · DOI · Paper page
Cited by
Sorted by citations
The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders
Carmona, S., Zahs, K., Wu, E., Dakin, K., Bras, J., & Guerreiro, R. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30232-1 · Cited by 244 · see citing works
Genetics of Alzheimer’s disease: An East Asian perspective
Miyashita, A., Kikuchi, M., Hara, N., & Ikeuchi, T. (2023) · Journal of Human Genetics · doi:10.1038/s10038-022-01050-z · Cited by 64 · see citing works
- Authors
- Bonham, L. W., Sirkis, D. W., Fan, J., Aparicio, R. E., Tse, M., Ramos, E. M., Wang, Q., Coppola, G., Rosen, H. J., Miller, B. L., & Yokoyama, J. S.
- Affiliations
- University of California, San Francisco (US)
- Howard Hughes Medical Institute (US)
- University of California, Los Angeles (US)
- Corresponding author
- Yokoyama, Jennifer S.
- ORCID
- Venue
- Neurocase
- Publisher
- Informa UK Limited
- Published
- 2017-01-02
- Volume
- 23
- Issue
- 1
- Pages
- 65-69
- ISSN
- 1355-4794 (ISSN-L)
- 1465-3656
- PMC
- PMC5639900
- OpenAlex
- W2605301967
- Cited by
- 10
- References
- 8
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 2
- FWCI
- 0.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurocase (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Larry L. Hillblom Foundation (2012-A-015-FEL, 2016-A-005-SUP)
- National Institute on Aging (F32 AG050404, K01 AG049152, K24 AG045333, P01 AG1972403, P50 AG023501)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, Alzheimer's disease, microglia, neuroinflammation, cell surface expression, genetic risk, Chinese population, genetic diversity
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cognition Disorders, Female, Humans, Male, Membrane Glycoproteins, Molecular Biology, Receptors, Immunologic, Transfection, Cohort Studies, Biotinylation, Polymorphism, Single Nucleotide, Asian People, HEK293 Cells
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