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

Thorkild I.A. Sørensen, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank)

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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.

Original languageEnglish
JournalActa Neuropathologica
Volume138
Issue number2
Pages (from-to)237-250
ISSN0001-6322
DOIs
Publication statusPublished - Aug 2019

Fingerprint

Lewy Body Disease
Alzheimer Disease
Mutation
Neurodegenerative Diseases
Alleles
Proxy
Sample Size
Parkinson Disease
Immune System
Pharmaceutical Preparations

Keywords

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

Cite this

Sørensen, Thorkild I.A. ; DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank). / 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 ; Vol. 138, No. 2. pp. 237-250.
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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.",
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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. / Sørensen, Thorkild I.A.; DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank).

In: Acta Neuropathologica, Vol. 138, No. 2, 08.2019, p. 237-250.

Research output: Contribution to journalJournal articleResearchpeer-review

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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 - Nohr, Ellen A

AU - Sørensen, Thorkild I.A.

AU - Christensen, Kaare

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

PY - 2019/8

Y1 - 2019/8

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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; 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

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 - Parkinson’s disease

KW - Phospholipase C Gamma 2

KW - PLCG2

KW - Progressive supranuclear palsy

U2 - 10.1007/s00401-019-02026-8

DO - 10.1007/s00401-019-02026-8

M3 - Journal article

VL - 138

SP - 237

EP - 250

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 2

ER -