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Open Access 01-08-2019 | Amyotrophic Lateral Sclerosis | Original Paper

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

Authors: Sven J. van der Lee, Olivia J. Conway, Iris Jansen, Minerva M. Carrasquillo, Luca Kleineidam, Erik van den Akker, Isabel Hernández, Kristel R. van Eijk, Najada Stringa, Jason A. Chen, Anna Zettergren, Till F. M. Andlauer, Monica Diez-Fairen, Javier Simon-Sanchez, Alberto Lleó, Henrik Zetterberg, Marianne Nygaard, Cornelis Blauwendraat, Jeanne E. Savage, Jonas Mengel-From, Sonia Moreno-Grau, Michael Wagner, Juan Fortea, Michael J. Keogh, Kaj Blennow, Ingmar Skoog, Manuel A. Friese, Olga Pletnikova, Miren Zulaica, Carmen Lage, Itziar de Rojas, Steffi Riedel-Heller, Ignacio Illán-Gala, Wei Wei, Bernard Jeune, Adelina Orellana, Florian Then Bergh, Xue Wang, Marc Hulsman, Nina Beker, Niccolo Tesi, Christopher M. Morris, Begoña Indakoetxea, Lyduine E. Collij, Martin Scherer, Estrella Morenas-Rodríguez, James W. Ironside, Bart N. M. van Berckel, Daniel Alcolea, Heinz Wiendl, Samantha L. Strickland, Pau Pastor, Eloy Rodríguez Rodríguez, Bradley F. Boeve, Ronald C. Petersen, Tanis J. Ferman, Jay A. van Gerpen, Marcel J. T. Reinders, Ryan J. Uitti, Lluís Tárraga, Wolfgang Maier, Oriol Dols-Icardo, Amit Kawalia, Maria Carolina Dalmasso, Mercè Boada, Uwe K. Zettl, Natasja M. van Schoor, Marian Beekman, Mariet Allen, Eliezer Masliah, Adolfo López de Munain, Alexander Pantelyat, Zbigniew K. Wszolek, Owen A. Ross, Dennis W. Dickson, Neill R. Graff-Radford, David Knopman, Rosa Rademakers, Afina W. Lemstra, Yolande A. L. Pijnenburg, Philip Scheltens, Thomas Gasser, Patrick F Chinnery, Bernhard Hemmer, Martijn A. Huisman, Juan Troncoso, Fermin Moreno, Ellen A. Nohr, Thorkild I. A. Sørensen, Peter Heutink, Pascual Sánchez-Juan, Danielle Posthuma, Jordi Clarimón, Kaare Christensen, Nilüfer Ertekin-Taner, Sonja W. Scholz, Alfredo Ramirez, Agustín Ruiz, Eline Slagboom, Wiesje M. van der Flier, Henne Holstege, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), The GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group

Published in: Acta Neuropathologica | Issue 2/2019

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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Title: 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
Authors: Sven J. van der Lee
Olivia J. Conway
Iris Jansen
Minerva M. Carrasquillo
Luca Kleineidam
Erik van den Akker
Isabel Hernández
Kristel R. van Eijk
Najada Stringa
Jason A. Chen
Anna Zettergren
Till F. M. Andlauer
Monica Diez-Fairen
Javier Simon-Sanchez
Alberto Lleó
Henrik Zetterberg
Marianne Nygaard
Cornelis Blauwendraat
Jeanne E. Savage
Jonas Mengel-From
Sonia Moreno-Grau
Michael Wagner
Juan Fortea
Michael J. Keogh
Kaj Blennow
Ingmar Skoog
Manuel A. Friese
Olga Pletnikova
Miren Zulaica
Carmen Lage
Itziar de Rojas
Steffi Riedel-Heller
Ignacio Illán-Gala
Wei Wei
Bernard Jeune
Adelina Orellana
Florian Then Bergh
Xue Wang
Marc Hulsman
Nina Beker
Niccolo Tesi
Christopher M. Morris
Begoña Indakoetxea
Lyduine E. Collij
Martin Scherer
Estrella Morenas-Rodríguez
James W. Ironside
Bart N. M. van Berckel
Daniel Alcolea
Heinz Wiendl
Samantha L. Strickland
Pau Pastor
Eloy Rodríguez Rodríguez
Bradley F. Boeve
Ronald C. Petersen
Tanis J. Ferman
Jay A. van Gerpen
Marcel J. T. Reinders
Ryan J. Uitti
Lluís Tárraga
Wolfgang Maier
Oriol Dols-Icardo
Amit Kawalia
Maria Carolina Dalmasso
Mercè Boada
Uwe K. Zettl
Natasja M. van Schoor
Marian Beekman
Mariet Allen
Eliezer Masliah
Adolfo López de Munain
Alexander Pantelyat
Zbigniew K. Wszolek
Owen A. Ross
Dennis W. Dickson
Neill R. Graff-Radford
David Knopman
Rosa Rademakers
Afina W. Lemstra
Yolande A. L. Pijnenburg
Philip Scheltens
Thomas Gasser
Patrick F Chinnery
Bernhard Hemmer
Martijn A. Huisman
Juan Troncoso
Fermin Moreno
Ellen A. Nohr
Thorkild I. A. Sørensen
Peter Heutink
Pascual Sánchez-Juan
Danielle Posthuma
Jordi Clarimón
Kaare Christensen
Nilüfer Ertekin-Taner
Sonja W. Scholz
Alfredo Ramirez
Agustín Ruiz
Eline Slagboom
Wiesje M. van der Flier
Henne Holstege
DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank)
EADB (Alzheimer Disease European DNA biobank)
IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium)
IPDGC (The International Parkinson Disease Genomics Consortium)
RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia)
Netherlands Brain Bank (NBB)
The GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group
Publication date: 01-08-2019
Publisher: Springer Berlin Heidelberg
Keywords: Amyotrophic Lateral Sclerosis
Frontotemporal Dementia
Multiple Sclerosis
Frontotemporal Dementia
Alzheimer's Disease
Dementia
Alzheimer's Disease
Parkinson's Disease
Dementia
Progressive Supranuclear Palsy
Published in: Acta Neuropathologica / Issue 2/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02026-8

At a glance: The STEP trials

Springer Medicine

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

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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