| 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 |
| Journal: | Acta Neuropathologica |
| Published: | 26 May 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/31131421/ |
| DOI: | https://doi.org/10.1007/s00401-019-02026-8 |
| URL: | https://link.springer.com/content/pdf/10.1007/s00401-019-02026-8.pdf |
| Citations: | 95 (27 in last 2 years) as of 8 Aug 2024 |
Publication 3918
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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.</p>
101 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
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