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

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

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
JournalActa Neuropathologica
Early online date27 May 2019
DOIs
Publication statusPublished - 2019

Cite this

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 (2019). 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. Acta Neuropathologica. https://doi.org/10.1007/s00401-019-02026-8, https://doi.org/10.1007/s00401-019-02026-8
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. / 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. In: Acta Neuropathologica. 2019.
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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",
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.",
author = "{DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank)} and {EADB (Alzheimer Disease European DNA biobank)} and {IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium)} and {IPDGC (The International Parkinson Disease Genomics Consortium)} and {RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia)} and {Netherlands Brain Bank (NBB)} and {The GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group} and {van der Lee}, {Sven J.} and Conway, {Olivia J.} and Iris Jansen and Carrasquillo, {Minerva M.} and Luca Kleineidam and {van den Akker}, Erik and Isabel Hern{\'a}ndez and {van Eijk}, {Kristel R.} and Najada Stringa and Chen, {Jason A.} and Anna Zettergren and Andlauer, {Till F. M.} and Monica Diez-Fairen and Javier Simon-Sanchez and Alberto Lle{\'o} and Henrik Zetterberg and Marianne Nygaard and Cornelis Blauwendraat and Savage, {Jeanne E.} and Jonas Mengel-From and Sonia Moreno-Grau and Michael Wagner and Juan Fortea and Keogh, {Michael J.} and Kaj Blennow and Ingmar Skoog and Friese, {Manuel A.} and Olga Pletnikova and Miren Zulaica and Carmen Lage and {de Rojas}, Itziar and Steffi Riedel-Heller and Ignacio Ill{\'a}n-Gala and Wei Wei and Bernard Jeune and Marc Hulsman and Nina Beker and Niccolo Tesi and Collij, {Lyduine E.} and {van Berckel}, {Bart N. M.} and Reinders, {Marcel J. T.} and {van Schoor}, {Natasja M.} and Lemstra, {Afina W.} and Pijnenburg, {Yolande A. L.} and Philip Scheltens and Huisman, {Martijn A.} and Peter Heutink and Danielle Posthuma and {van der Flier}, {Wiesje M.} and Henne Holstege",
year = "2019",
doi = "10.1007/s00401-019-02026-8",
language = "English",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",

}

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 2019, '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' Acta Neuropathologica. https://doi.org/10.1007/s00401-019-02026-8, https://doi.org/10.1007/s00401-019-02026-8

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. / 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.

In: Acta Neuropathologica, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

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 - Hulsman, Marc

AU - Beker, Nina

AU - Tesi, Niccolo

AU - Collij, Lyduine E.

AU - van Berckel, Bart N. M.

AU - Reinders, Marcel J. T.

AU - van Schoor, Natasja M.

AU - Lemstra, Afina W.

AU - Pijnenburg, Yolande A. L.

AU - Scheltens, Philip

AU - Huisman, Martijn A.

AU - Heutink, Peter

AU - Posthuma, Danielle

AU - van der Flier, Wiesje M.

AU - Holstege, Henne

PY - 2019

Y1 - 2019

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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/31131421

U2 - 10.1007/s00401-019-02026-8

DO - 10.1007/s00401-019-02026-8

M3 - Article

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

ER -

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) et al. 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. Acta Neuropathologica. 2019. https://doi.org/10.1007/s00401-019-02026-8, https://doi.org/10.1007/s00401-019-02026-8