Journal Article

DZNE-2020-07162

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

van der Lee, S. J. (Corresponding author) ; Conway, O. J. ; Jansen, I. ; Carrasquillo, M. M. ; Kleineidam, L.DZNE* ; van den Akker, E. ; Hernández, I. ; van Eijk, K. R. ; Stringa, N. ; Chen, J. A. ; Zettergren, A. ; Andlauer, T. F. M. ; Diez-Fairen, M. ; Simon Sanchez, J.DZNE* ; Lleó, A. ; Zetterberg, H. ; Nygaard, M. ; Blauwendraat, C. ; Savage, J. E. ; Mengel-From, J. ; Moreno-Grau, S. ; Wagner, M.DZNE* ; Fortea, J. ; Keogh, M. J. ; Blennow, K. ; Skoog, I. ; Friese, M. A. ; Pletnikova, O. ; Zulaica, M. ; Lage, C. ; de Rojas, I. ; Riedel-Heller, S. ; Illán-Gala, I. ; Wei, W. ; Jeune, B. ; Orellana, A. ; Then Bergh, F. ; Wang, X. ; Hulsman, M. ; Beker, N. ; Tesi, N. ; Morris, C. M. ; Indakoetxea, B. ; Collij, L. E. ; Scherer, M. ; Morenas-Rodríguez, E. ; Ironside, J. W. ; van Berckel, B. N. M. ; Alcolea, D. ; Wiendl, H. ; Strickland, S. L. ; Pastor, P. ; Rodríguez Rodríguez, E. ; DESGESCO ; EADB ; IFGC ; IPDGC ; RiMod-FTD ; Bank, N. B. ; Boeve, B. F. ; Petersen, R. C. ; Ferman, T. J. ; van Gerpen, J. A. ; Reinders, M. J. T. ; Uitti, R. J. ; Tárraga, L. ; Maier, W.DZNE* ; Dols-Icardo, O. ; Kawalia, A. ; Dalmasso, M. C. ; Boada, M. ; Zettl, U. K. ; van Schoor, N. M. ; Beekman, M. ; Allen, M. ; Masliah, E. ; de Munain, A. L. ; Pantelyat, A. ; Wszolek, Z. K. ; Ross, O. A. ; Dickson, D. W. ; Graff-Radford, N. R. ; Knopman, D. ; Rademakers, R. ; Lemstra, A. W. ; Pijnenburg, Y. A. L. ; Scheltens, P. ; Gasser, T. ; Chinnery, P. F. ; Hemmer, B. ; Huisman, M. A. ; Troncoso, J. ; Moreno, F. ; Nohr, E. A. ; Sørensen, T. I. A. ; Heutink, P.DZNE* ; Sánchez-Juan, P. ; Posthuma, D. ; GIFT ; Clarimón, J. ; Christensen, K. ; Ertekin-Taner, N. ; Scholz, S. W. ; Ramirez, A. ; Ruiz, A. ; Slagboom, E. ; van der Flier, W. M. ; Holstege, H. ; Coppola, G. ; Karydas, A. M. ; Varpetian, A. ; Foroud, T. M. ; Levey, A. I. ; Kukull, W. A. ; Mendez, M. F. ; Ringman, J. ; Chui, H. ; Cotman, C. ; DeCarli, C. ; Miller, B. L. ; Geschwind, D. H.

2019
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-019-02026-8

Abstract: The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Keyword(s): Alleles (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Brain: immunology (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Dementia: genetics (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Genome-Wide Association Study (MeSH) ; Humans (MeSH) ; Lewy Body Disease: genetics (MeSH) ; Longevity: genetics (MeSH) ; Microglia: metabolism (MeSH) ; Multiple Sclerosis: genetics (MeSH) ; Mutation (MeSH) ; Neuroimaging (MeSH) ; Parkinson Disease: genetics (MeSH) ; Phospholipase C gamma: genetics (MeSH) ; Risk (MeSH)

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Contributing Institute(s):

1. Neuropsychology (AG Wagner)
2. Genome Biology of Neurodegenerative Diseases (AG Heutink 1)
3. U Clinical Researchers - Bonn (U Clinical Researchers - Bonn)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)
2. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2019

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Database coverage:
; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 15 ; JCR ; SCOPUS ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article (Erratum/Correction) van der Lee, S. J. (Corresponding author) ; Conway, O. J. ; Jansen, I. ; et al
Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.
Acta neuropathologica 139(5), 959-962 (2020) [10.1007/s00401-019-02107-8]2020   Files  Fulltext by Pubmed Central BibTeX | EndNote: XML, Text | RIS

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