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

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 - 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 - Wiendl, Heinz

AU - Strickland, Samantha L

AU - Pastor, Pau

AU - Rodríguez Rodríguez, Eloy

AU - Boeve, Bradley F

AU - Petersen, Ronald C

AU - Ferman, Tanis J

AU - van Gerpen, Jay A

AU - Reinders, Marcel J T

AU - Uitti, Ryan J

AU - Tárraga, Lluís

AU - Maier, Wolfgang

AU - Dols-Icardo, Oriol

AU - Kawalia, Amit

AU - Dalmasso, Maria Carolina

AU - Boada, Mercè

AU - Zettl, Uwe K

AU - van Schoor, Natasja M

AU - Beekman, Marian

AU - Allen, Mariet

AU - Masliah, Eliezer

AU - de Munain, Adolfo López

AU - Pantelyat, Alexander

AU - Wszolek, Zbigniew K

AU - Ross, Owen A

AU - Dickson, Dennis W

AU - Graff-Radford, Neill R

AU - Knopman, David

AU - Rademakers, Rosa

AU - Lemstra, Afina W

AU - Pijnenburg, Yolande A L

AU - Scheltens, Philip

AU - Gasser, Thomas

AU - Chinnery, Patrick F

AU - Hemmer, Bernhard

AU - Huisman, Martijn A

AU - Troncoso, Juan

AU - Moreno, Fermin

AU - Nohr, Ellen A

AU - Sørensen, Thorkild I A

AU - Heutink, Peter

AU - Sánchez-Juan, Pascual

AU - Posthuma, Danielle

AU - Clarimón, Jordi

AU - Christensen, Kaare

AU - Ertekin-Taner, Nilüfer

AU - Scholz, Sonja W

AU - Ramirez, Alfredo

AU - Ruiz, Agustín

AU - Slagboom, Eline

AU - van der Flier, Wiesje M

AU - Holstege, Henne

AU - DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank)

PY - 2019/8

Y1 - 2019/8

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 - Journal Article

U2 - 10.1007/s00401-019-02026-8

DO - 10.1007/s00401-019-02026-8

M3 - SCORING: Journal article

C2 - 31131421

VL - 138

SP - 237

EP - 250

JO - ACTA NEUROPATHOL

JF - ACTA NEUROPATHOL

SN - 0001-6322

IS - 2

ER -