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

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...

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Autores: van der Lee, Sven J.|||0000-0003-1606-8643, Conway, Olivia J., Jansen, Iris E.|||0000-0003-1901-8131, Carrasquillo, Minerva M., Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel|||0000-0001-8119-393X, Van Eijk, Kristel R., Stringa, Najada|||0000-0001-6350-452X, Chen, Jason A., Zettergren, Anna|||0000-0002-7182-8417, Andlauer, Till F. M.|||0000-0002-2917-5889, Diez-Fairen, Monica|||0000-0003-1882-0309, Simon-Sanchez, Javier, Lleó, Alberto|||0000-0002-2568-5478, Zetterberg, Henrik|||0000-0003-3930-4354, Nygaard, Marianne|||0000-0003-0703-2665, Blauwendraat, Cornelis|||0000-0001-9358-8111, Savage, Jeanne E., Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan|||0000-0002-1340-638X, Keogh, Michael J., Blennow, Kaj|||0000-0002-1890-4193, Skoog, Ingmar, Friese, Manuel A., Pletnikova, Olga|||0000-0001-6516-4944, Zulaica, Miren, Lage, Carmen|||0000-0003-1703-121X, De Rojas, Itziar|||0000-0002-2148-381X, Riedel-Heller, Steffi|||0000-0003-4321-6090, Illán-Gala, Ignacio|||0000-0002-5418-2052, Wei, Wei, Jeune, Bernard, Orellana del Río, Adelina|||0000-0002-0204-1944, Then Bergh, Florian, Wang, Xue, Hulsman, Marc|||0000-0002-9889-3606, Beker, Nina, Tesi, Niccolo|||0000-0002-1413-5091, Morris, Christopher M., Indakoetxea, Begoña, Collij, Lyduine E., Scherer, Martin, Morenas-Rodríguez, Estrella|||0000-0002-7591-6051, Ironside, James W., van Berckel, Bart N. M., Alcolea, Daniel|||0000-0002-3819-3245, Wiendl, Heinz|||0000-0003-4310-3432, Strickland, Samantha L., Pastor, Pau|||0000-0002-7493-8777, Rodríguez-Rodríguez, Eloy|||0000-0001-7742-677X, Boeve, Bradley, Petersen, Ronald C., Ferman, Tanis J., van Gerpen, Jay A., Reinders, Marcel J. T.|||0000-0002-1148-1562, Uitti, Ryan J., Tárraga, Lluís|||0000-0002-8423-946X, Maier, Wolfgang, Dols Icardo, Oriol|||0000-0003-2656-8748, Kawalia, Amit, Dalmasso, Maria Carolina|||0000-0002-4901-9955, Boada, Mercè|||0000-0003-2617-3009, Zettl, Uwe K., van Schoor, Natasja M., Beekman, Marian|||0000-0003-0585-6206, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K.|||0000-0001-5487-1053, Ross, Owen A.|||0000-0003-4813-756X, Dickson, Dennis W.|||0000-0001-7189-7917, Graff-Radford, Neill R., Knopman, David, Rademakers, Rosa, Lemstra, Afina W.|||0000-0002-8933-3260, Pijnenburg, Yolande|||0000-0003-2464-1905, Scheltens, Philip|||0000-0002-1046-6408, Gasser, Thomas|||0000-0003-4882-2647, Chinnery, Patrick F., Hemmer, Bernhard|||0000-0001-5985-6784, Huisman, Martijn A., Troncoso, Juan, Moreno, Fermin|||0000-0001-5200-3164, Nohr, Ellen A., Sørensen, Thorkild I. A.|||0000-0003-4821-430X, Heutink, Peter|||0000-0001-5218-1737, Sánchez-Juan, Pascual|||0000-0002-6081-8037, Posthuma, Danielle|||0000-0001-7582-2365, Clarimón, Jordi|||0000-0002-6824-6942, Christensen, Kaare|||0000-0002-5429-5292, Ertekin-Taner, Nilüfer, Scholz, Sonja|||0000-0002-6623-0429, Ramirez, Alfredo|||0000-0003-4991-763X, Ruiz Laza, Agustín|||0000-0003-2633-2495, Slagboom, Eline, van der Flier, Wiesje M.|||0000-0001-8766-6224, Holstege, Henne|||0000-0002-7688-3087
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:226469
Acceso en línea:https://ddd.uab.cat/record/226469
https://dx.doi.org/urn:doi:10.1007/s00401-019-02026-8
Access Level:acceso abierto
Palabra clave:Alzheimer's disease
Frontotemporal dementia
Dementia with Lewy bodies
Progressive supranuclear palsy
Parkinson's disease
Amyotrophic lateral sclerosis
Multiple sclerosis
Neurodegenerative disease
Longevity
PLCG2
Phospholipase C Gamma 2
Descripción
Sumario: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.

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