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*, 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-FromSonia 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, Ellen A Nohr, Thorkild I.A. Sørensen, Kaare Christensen, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank)

*Kontaktforfatter for dette arbejde

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Abstrakt

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.
OriginalsprogEngelsk
TidsskriftActa Neuropathologica
Vol/bind138
Udgave nummer2
Sider (fra-til)237-250
ISSN0001-6322
DOI
StatusUdgivet - aug. 2019

Emneord

  • Alzheimer’s disease; Amyotrophic lateral sclerosis; Dementia with Lewy bodies; Frontotemporal dementia; Longevity; Multiple sclerosis; Neurodegenerative disease; PLCG2; Parkinson’s disease; Phospholipase C Gamma 2; Progressive supranuclear palsy

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