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
Sven J. van der Lee(Amsterdam Neuroscience), EADB (Alzheimer Disease European DNA biobank)(Mayo Clinic in Florida), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia)(Amsterdam Neuroscience), Netherlands Brain Bank (NBB)(Mayo Clinic in Florida), The GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group(University of Bonn), Olivia J. Conway(Leiden University Medical Center), Iris E. Jansen(Amsterdam Neuroscience), Minerva M. Carrasquillo(University Medical Center Utrecht), Luca Kleineidam(University of Bonn), Erik B. van den Akker(University of California, Los Angeles), Isabel Hernández(Biomedical Research Networking Center on Neurodegenerative Diseases), Kristel R. van Eijk(University Medical Center Utrecht), Najada Stringa(University Hospital Mútua de Terrassa), Jason Chen(University of California, Los Angeles), Anna Zettergren(Biomedical Research Networking Center on Neurodegenerative Diseases), Till F. M. Andlauer(Sahlgrenska University Hospital), Mónica Díez-Fairén(University of Southern Denmark), Javier Simón‐Sánchez(German Center for Neurodegenerative Diseases), Alberto Lleó(Universitat Autònoma de Barcelona), Henrik Zetterberg(University of Southern Denmark), Marianne Nygaard(University of Southern Denmark), Cornelis Blauwendraat(University of Bonn), Jeanne E. Savage(Biomedical Research Networking Center on Neurodegenerative Diseases), Jonas Mengel‐From(University of Southern Denmark), Sonia Moreno–Grau(Sahlgrenska University Hospital), Michael Wagner(University of Bonn), Juan Fortea(Universitat Autònoma de Barcelona), Michael J. Keogh(Johns Hopkins University), Kaj Blennow(Sahlgrenska University Hospital), Ingmar Skoog(Biomedical Research Networking Center on Neurodegenerative Diseases), Manuel A. Friese(Universität Hamburg), Olga Pletnikova(Johns Hopkins University), Miren Zulaica(Biomedical Research Networking Center on Neurodegenerative Diseases), Carmen Lage(University of Cambridge), Itziar de Rojas(University of Southern Denmark), Steffi G. Riedel‐Heller(Fundació ACE), Ignacio Illán‐Gala(Universitat Autònoma de Barcelona), Wei Wei(University of Cambridge), Bernard Jeune(University of Southern Denmark), Adelina Orellana(Biomedical Research Networking Center on Neurodegenerative Diseases), Florian Then Bergh(Competence Network Multiple Sclerosis), Xue Wang(Mayo Clinic in Florida), Marc Hulsman(Biomedical Research Networking Center on Neurodegenerative Diseases), Nina Beker(Amsterdam Neuroscience), Niccoló Tesi(Universität Hamburg), Christopher M. Morris(Biomedical Research Networking Center on Neurodegenerative Diseases), Begoña Indakoetxea(Biomedical Research Networking Center on Neurodegenerative Diseases), Lyduine E. Collij(Amsterdam Neuroscience), Martin Scherer(Universität Hamburg), Estrella Morenas‐Rodríguez(Universitat Autònoma de Barcelona), James W. Ironside(Mayo Clinic in Florida), Bart N.M. van Berckel(University Hospital Mútua de Terrassa), Daniel Alcolea(Universitat Autònoma de Barcelona), Heinz Wiendl(Mayo Clinic), Samantha L. Strickland(Mayo Clinic), Pau Pástor(University Hospital Mútua de Terrassa), Eloy Rodríguez‐Rodríguez(Biomedical Research Networking Center on Neurodegenerative Diseases), Bradley F. Boeve(Mayo Clinic), Ronald C. Petersen(Mayo Clinic), Tanis J. Ferman(Biomedical Research Networking Center on Neurodegenerative Diseases), Jay A. van Gerpen(German Center for Neurodegenerative Diseases), Marcel Reinders(Biomedical Research Networking Center on Neurodegenerative Diseases), Ryan J. Uitti(Mayo Clinic in Florida), Lluís Tárraga(Biomedical Research Networking Center on Neurodegenerative Diseases), Wolfgang Maier(University of Bonn), Oriol Dols‐Icardo(Universitat Autònoma de Barcelona), Amit Kawalia(Amsterdam University Medical Centers), Carolina Dalmasso(Consejo Nacional de Investigaciones Científicas y Técnicas), Merçé Boada(Biomedical Research Networking Center on Neurodegenerative Diseases), Uwe K. Zettl(National Institutes of Health), Natasja M. van Schoor(Biomedical Research Networking Center on Neurodegenerative Diseases), Marian Beekman(Johns Hopkins University), Mariet Allen(Mayo Clinic in Florida), Eliezer Masliah(National Institutes of Health), Adolfo López de Munain(Biomedical Research Networking Center on Neurodegenerative Diseases), Alexander Pantelyat(Johns Hopkins University), Zbigniew K. Wszołek(Mayo Clinic), Owen A. Ross(Mayo Clinic in Florida), Dennis W. Dickson(Amsterdam Neuroscience), Caroline Graff(Amsterdam Neuroscience), David S. Knopman(Mayo Clinic), Rosa Rademakers(Hertie Institute for Clinical Brain Research), Afina W. Lemstra(University of Cambridge), Yolande A.L. Pijnenburg(Amsterdam Neuroscience), Philip Scheltens(Amsterdam Neuroscience), Thomas Gasser(Johns Hopkins University), Patrick F. Chinnery(University of Cambridge), Bernhard Hemmer(University of Southern Denmark), Martijn Huisman(Novo Nordisk Foundation), Juan C. Troncoso(Johns Hopkins University), Fermín Moreno(Biomedical Research Networking Center on Neurodegenerative Diseases), Ellen A. Nøhr(University of Southern Denmark), Thorkild I. A. Sørensen(Universitat Autònoma de Barcelona), Peter Heutink(University of Southern Denmark), Pascual Sánchez‐Juan(Biomedical Research Networking Center on Neurodegenerative Diseases), Daniëlle Posthuma(Amsterdam Neuroscience), Jordi Clarimón(Universitat Autònoma de Barcelona), Kaare Christensen(University of Southern Denmark), Nilüfer Ertekin‐Taner(Mayo Clinic in Florida), Sonja W. Scholz(Johns Hopkins University), Alfredo Ramı́rez(University of Bonn), Agustı́n Ruiz(Biomedical Research Networking Center on Neurodegenerative Diseases), P. Eline Slagboom(Leiden University Medical Center), Wiesje M. van der Flier(Amsterdam Neuroscience), Henne Holstege(Amsterdam Neuroscience)
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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 PLCγ2 pathway as drug-target.
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