Variant of TREM2 associated with the risk of Alzheimer's disease
Background: Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. Methods: We obtained the genome seque...
Published in: | New England Journal of Medicine |
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Online Access: | http://repub.eur.nl/pub/67838 https://doi.org/10.1056/NEJMoa1211103 |
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ftunivrotterdam:oai:repub.eur.nl:67838 2023-07-16T03:59:12+02:00 Variant of TREM2 associated with the risk of Alzheimer's disease Jonsson, T. (Thorlakur) Stefansson, H. (Hreinn) Wolf, C. (Christiane) Jonsdottir, I. (Ingileif) Jonsson, P.V. (Palmi) SnÆdal, J. (Jon) Björnsson, S. (Sigurbjörn) Huttenlocher, J. (Johanna) Levey, A.I. (Allan) Lah, J.J. (James) Rujescu, D. (Dan) Hampel, H. (Harald) Giegling, I. (Ina) Andreassen, O.A. (Ole) Engedal, K. (Knut) Ulstein, I. (Ingun) Djurovic, S. (Srdjan) Ibrahim-Verbaas, C.A. (Carla) Hofman, A. (Albert) Ikram, M.A. (Arfan) Duijn, C.M. (Cornelia) van Thorsteinsdottir, U. (Unnur) Kong, A. (Augustine) Zwart, J-A. (John-Anker) 2013-01-10 http://repub.eur.nl/pub/67838 https://doi.org/10.1056/NEJMoa1211103 en eng info:eu-repo/grantAgreement/EC/FP7/201413 http://repub.eur.nl/pub/67838 doi:10.1056/NEJMoa1211103 urn:hdl:1765/67838 info:eu-repo/semantics/openAccess New England Journal of Medicine vol. 368 no. 2, pp. 107-116 info:eu-repo/semantics/article 2013 ftunivrotterdam https://doi.org/10.1056/NEJMoa1211103 2023-06-26T22:19:35Z Background: Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. Methods: We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case-control series from the United States, Norway, the Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. Results: A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P = 3.42×10-10). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P = 2.1×10-12 in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P = 0.003). Conclusions: Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.) Copyright Article in Journal/Newspaper Iceland RePub - Publications from Erasmus University, Rotterdam Norway New England Journal of Medicine 368 2 107 116 |
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Open Polar |
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RePub - Publications from Erasmus University, Rotterdam |
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ftunivrotterdam |
language |
English |
description |
Background: Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. Methods: We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case-control series from the United States, Norway, the Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. Results: A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P = 3.42×10-10). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P = 2.1×10-12 in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P = 0.003). Conclusions: Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.) Copyright |
format |
Article in Journal/Newspaper |
author |
Jonsson, T. (Thorlakur) Stefansson, H. (Hreinn) Wolf, C. (Christiane) Jonsdottir, I. (Ingileif) Jonsson, P.V. (Palmi) SnÆdal, J. (Jon) Björnsson, S. (Sigurbjörn) Huttenlocher, J. (Johanna) Levey, A.I. (Allan) Lah, J.J. (James) Rujescu, D. (Dan) Hampel, H. (Harald) Giegling, I. (Ina) Andreassen, O.A. (Ole) Engedal, K. (Knut) Ulstein, I. (Ingun) Djurovic, S. (Srdjan) Ibrahim-Verbaas, C.A. (Carla) Hofman, A. (Albert) Ikram, M.A. (Arfan) Duijn, C.M. (Cornelia) van Thorsteinsdottir, U. (Unnur) Kong, A. (Augustine) Zwart, J-A. (John-Anker) |
spellingShingle |
Jonsson, T. (Thorlakur) Stefansson, H. (Hreinn) Wolf, C. (Christiane) Jonsdottir, I. (Ingileif) Jonsson, P.V. (Palmi) SnÆdal, J. (Jon) Björnsson, S. (Sigurbjörn) Huttenlocher, J. (Johanna) Levey, A.I. (Allan) Lah, J.J. (James) Rujescu, D. (Dan) Hampel, H. (Harald) Giegling, I. (Ina) Andreassen, O.A. (Ole) Engedal, K. (Knut) Ulstein, I. (Ingun) Djurovic, S. (Srdjan) Ibrahim-Verbaas, C.A. (Carla) Hofman, A. (Albert) Ikram, M.A. (Arfan) Duijn, C.M. (Cornelia) van Thorsteinsdottir, U. (Unnur) Kong, A. (Augustine) Zwart, J-A. (John-Anker) Variant of TREM2 associated with the risk of Alzheimer's disease |
author_facet |
Jonsson, T. (Thorlakur) Stefansson, H. (Hreinn) Wolf, C. (Christiane) Jonsdottir, I. (Ingileif) Jonsson, P.V. (Palmi) SnÆdal, J. (Jon) Björnsson, S. (Sigurbjörn) Huttenlocher, J. (Johanna) Levey, A.I. (Allan) Lah, J.J. (James) Rujescu, D. (Dan) Hampel, H. (Harald) Giegling, I. (Ina) Andreassen, O.A. (Ole) Engedal, K. (Knut) Ulstein, I. (Ingun) Djurovic, S. (Srdjan) Ibrahim-Verbaas, C.A. (Carla) Hofman, A. (Albert) Ikram, M.A. (Arfan) Duijn, C.M. (Cornelia) van Thorsteinsdottir, U. (Unnur) Kong, A. (Augustine) Zwart, J-A. (John-Anker) |
author_sort |
Jonsson, T. (Thorlakur) |
title |
Variant of TREM2 associated with the risk of Alzheimer's disease |
title_short |
Variant of TREM2 associated with the risk of Alzheimer's disease |
title_full |
Variant of TREM2 associated with the risk of Alzheimer's disease |
title_fullStr |
Variant of TREM2 associated with the risk of Alzheimer's disease |
title_full_unstemmed |
Variant of TREM2 associated with the risk of Alzheimer's disease |
title_sort |
variant of trem2 associated with the risk of alzheimer's disease |
publishDate |
2013 |
url |
http://repub.eur.nl/pub/67838 https://doi.org/10.1056/NEJMoa1211103 |
geographic |
Norway |
geographic_facet |
Norway |
genre |
Iceland |
genre_facet |
Iceland |
op_source |
New England Journal of Medicine vol. 368 no. 2, pp. 107-116 |
op_relation |
info:eu-repo/grantAgreement/EC/FP7/201413 http://repub.eur.nl/pub/67838 doi:10.1056/NEJMoa1211103 urn:hdl:1765/67838 |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/10.1056/NEJMoa1211103 |
container_title |
New England Journal of Medicine |
container_volume |
368 |
container_issue |
2 |
container_start_page |
107 |
op_container_end_page |
116 |
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1771546760314880000 |