TY - JOUR
T1 - 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
AU - DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank)
AU - EADB (Alzheimer Disease European DNA biobank)
AU - IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium)
AU - IPDGC (The International Parkinson Disease Genomics Consortium)
AU - RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia)
AU - Netherlands Brain Bank (NBB)
AU - The GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group
AU - van der Lee, Sven J.
AU - Conway, Olivia J.
AU - Jansen, Iris
AU - Carrasquillo, Minerva M.
AU - Kleineidam, Luca
AU - van den Akker, Erik
AU - Hernández, Isabel
AU - van Eijk, Kristel R.
AU - Stringa, Najada
AU - Chen, Jason A.
AU - Zettergren, Anna
AU - Andlauer, Till F.M.
AU - Diez-Fairen, Monica
AU - Simon-Sanchez, Javier
AU - Lleó, Alberto
AU - Zetterberg, Henrik
AU - Nygaard, Marianne
AU - Blauwendraat, Cornelis
AU - Savage, Jeanne E.
AU - Mengel-From, Jonas
AU - Moreno-Grau, Sonia
AU - Wagner, Michael
AU - Fortea, Juan
AU - Keogh, Michael J.
AU - Blennow, Kaj
AU - Skoog, Ingmar
AU - Friese, Manuel A.
AU - Pletnikova, Olga
AU - Zulaica, Miren
AU - Lage, Carmen
AU - de Rojas, Itziar
AU - Riedel-Heller, Steffi
AU - Illán-Gala, Ignacio
AU - Wei, Wei
AU - Jeune, Bernard
AU - Orellana, Adelina
AU - Then Bergh, Florian
AU - Wang, Xue
AU - Hulsman, Marc
AU - Beker, Nina
AU - Tesi, Niccolo
AU - Morris, Christopher M.
AU - Indakoetxea, Begoña
AU - Collij, Lyduine E.
AU - Scherer, Martin
AU - Morenas-Rodríguez, Estrella
AU - Ironside, James W.
AU - van Berckel, Bart N.M.
AU - Alcolea, Daniel
AU - Hemmer, Bernhard
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - Amyotrophic lateral sclerosis
KW - Dementia with Lewy bodies
KW - Frontotemporal dementia
KW - Longevity
KW - Multiple sclerosis
KW - Neurodegenerative disease
KW - PLCG2
KW - Parkinson’s disease
KW - Phospholipase C Gamma 2
KW - Progressive supranuclear palsy
UR - https://www.scopus.com/pages/publications/85067685147
U2 - 10.1007/s00401-019-02026-8
DO - 10.1007/s00401-019-02026-8
M3 - Article
C2 - 31131421
AN - SCOPUS:85067685147
SN - 0001-6322
VL - 138
SP - 237
EP - 250
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 2
ER -