van der Lee, Sven J., Conway, Olivia J., Jansen, Iris, Carrasquillo, Minerva M., Kleineidam, Luca, van den Akker, Erik, Hernandez, Isabel, van Eijk, Kristel R., Stringa, Najada ORCID: 0000-0001-6350-452X, Chen, Jason A., Zettergren, Anna, Andlauer, Till F. M., Diez-Fairen, Monica ORCID: 0000-0003-1882-0309, Simon-Sanchez, Javier, Lleo, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E., Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael ORCID: 0000-0003-2589-6440, Fortea, Juan, Keogh, Michael J., Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A. ORCID: 0000-0001-6380-2420, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar ORCID: 0000-0002-2148-381X, Riedel-Heller, Steffi, Illan-Gala, Ignacio ORCID: 0000-0002-5418-2052, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Bergh, Florian Then, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M., Indakoetxea, Begona, Collij, Lyduine E., Scherer, Martin, Morenas-Rodriguez, Estrella, Ironside, James W., van Berckel, Bart N. M., Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L., Pastor, Pau ORCID: 0000-0002-7493-8777, Rodriguez Rodriguez, Eloy, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., van Gerpen, Jay A., Reinders, Marcel J. T., Uitti, Ryan J., Tarraga, Lluis, Maier, Wolfgang, Dols-Icardo, Oriol ORCID: 0000-0003-2656-8748, Kawalia, Amit, Dalmasso, Maria Carolina ORCID: 0000-0002-4901-9955, Boada, Merce, Zettl, Uwe K., van Schoor, Natasja M., Beekman, Marian, Allen, Mariet, Masliah, Eliezer, Lopez de Munain, Adolfo, Pantelyat, Alexander, Wszolek, Zbigniew K., Ross, Owen A., Dickson, Dennis W., Graff-Radford, Neill R., Knopman, David, Rademakers, Rosa, Lemstra, Afina W., Pijnenburg, Yolande A. L., Scheltens, Philip ORCID: 0000-0002-1046-6408, Gasser, Thomas, Chinnery, Patrick F., Hemmer, Bernhard, Huisman, Martijn A., Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A., Sorensen, Thorkild I. A., Heutink, Peter ORCID: 0000-0001-5218-1737, Sanchez-Juan, Pascual, Posthuma, Danielle, Clarimon, Jordi, Christensen, Kaare ORCID: 0000-0002-5429-5292, Ertekin-Taner, Nilufer, Scholz, Sonja W. ORCID: 0000-0002-6623-0429, Ramirez, Alfredo ORCID: 0000-0003-4991-763X, Ruiz, Agustin, Slagboom, Eline, van der Flier, Wiesje M. and Holstege, Henne (2019). 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 Neuropathol., 138 (2). S. 237 - 251. NEW YORK: SPRINGER. ISSN 1432-0533

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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 PLC gamma 2 pathway as drug-target.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
van der Lee, Sven J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Conway, Olivia J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jansen, IrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carrasquillo, Minerva M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kleineidam, LucaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van den Akker, ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hernandez, IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Eijk, Kristel R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stringa, NajadaUNSPECIFIEDorcid.org/0000-0001-6350-452XUNSPECIFIED
Chen, Jason A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zettergren, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andlauer, Till F. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diez-Fairen, MonicaUNSPECIFIEDorcid.org/0000-0003-1882-0309UNSPECIFIED
Simon-Sanchez, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lleo, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zetterberg, HenrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nygaard, MarianneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blauwendraat, CornelisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Savage, Jeanne E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mengel-From, JonasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moreno-Grau, SoniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, MichaelUNSPECIFIEDorcid.org/0000-0003-2589-6440UNSPECIFIED
Fortea, JuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keogh, Michael J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blennow, KajUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Skoog, IngmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friese, Manuel A.UNSPECIFIEDorcid.org/0000-0001-6380-2420UNSPECIFIED
Pletnikova, OlgaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zulaica, MirenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lage, CarmenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Rojas, ItziarUNSPECIFIEDorcid.org/0000-0002-2148-381XUNSPECIFIED
Riedel-Heller, SteffiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Illan-Gala, IgnacioUNSPECIFIEDorcid.org/0000-0002-5418-2052UNSPECIFIED
Wei, WeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jeune, BernardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Orellana, AdelinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bergh, Florian ThenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, XueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hulsman, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beker, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tesi, NiccoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morris, Christopher M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Indakoetxea, BegonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Collij, Lyduine E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scherer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morenas-Rodriguez, EstrellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ironside, James W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Berckel, Bart N. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alcolea, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiendl, HeinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strickland, Samantha L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pastor, PauUNSPECIFIEDorcid.org/0000-0002-7493-8777UNSPECIFIED
Rodriguez Rodriguez, EloyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boeve, Bradley F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petersen, Ronald C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferman, Tanis J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Gerpen, Jay A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinders, Marcel J. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uitti, Ryan J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tarraga, LluisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maier, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dols-Icardo, OriolUNSPECIFIEDorcid.org/0000-0003-2656-8748UNSPECIFIED
Kawalia, AmitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dalmasso, Maria CarolinaUNSPECIFIEDorcid.org/0000-0002-4901-9955UNSPECIFIED
Boada, MerceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zettl, Uwe K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Schoor, Natasja M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beekman, MarianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allen, MarietUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Masliah, EliezerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez de Munain, AdolfoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pantelyat, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wszolek, Zbigniew K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ross, Owen A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dickson, Dennis W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graff-Radford, Neill R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knopman, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rademakers, RosaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemstra, Afina W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pijnenburg, Yolande A. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheltens, PhilipUNSPECIFIEDorcid.org/0000-0002-1046-6408UNSPECIFIED
Gasser, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chinnery, Patrick F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hemmer, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huisman, Martijn A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Troncoso, JuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moreno, FerminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nohr, Ellen A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sorensen, Thorkild I. A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heutink, PeterUNSPECIFIEDorcid.org/0000-0001-5218-1737UNSPECIFIED
Sanchez-Juan, PascualUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Posthuma, DanielleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clarimon, JordiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Christensen, KaareUNSPECIFIEDorcid.org/0000-0002-5429-5292UNSPECIFIED
Ertekin-Taner, NiluferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scholz, Sonja W.UNSPECIFIEDorcid.org/0000-0002-6623-0429UNSPECIFIED
Ramirez, AlfredoUNSPECIFIEDorcid.org/0000-0003-4991-763XUNSPECIFIED
Ruiz, AgustinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Slagboom, ElineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Flier, Wiesje M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holstege, HenneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-133815
DOI: 10.1007/s00401-019-02026-8
Journal or Publication Title: Acta Neuropathol.
Volume: 138
Number: 2
Page Range: S. 237 - 251
Date: 2019
Publisher: SPRINGER
Place of Publication: NEW YORK
ISSN: 1432-0533
Language: English
Faculty: Faculty of Management, Economy and Social Sciences
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; PHOSPHOLIPASE-C-GAMMA; GENETIC ARCHITECTURE; INNATE IMMUNITY; ACTIVATION; APOE; AUTOIMMUNITY; INFLAMMATION; REPLICATION; MECHANISMSMultiple languages
Clinical Neurology; Neurosciences; PathologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13381

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