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-From; Sonia 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; Daniel Alcolea; Heinz Wiendl; Samantha L. Strickland; Pau Pastor; Eloy Rodríguez Rodríguez; Bradley F. Boeve; Ronald C. Petersen; Tanis J. Ferman; Jay A. van Gerpen; Marcel J.T. Reinders; Ryan J. Uitti; Lluís Tárraga; Wolfgang Maier; Oriol Dols-Icardo; Amit Kawalia; Maria Carolina Dalmasso; Mercè Boada; Uwe K. Zettl; Natasja M. van Schoor; Marian Beekman; Mariet Allen; Eliezer Masliah; Adolfo López de Munain; Alexander Pantelyat; Zbigniew K. Wszolek; Owen A. Ross; Dennis W. Dickson; Neill R. Graff-Radford; David Knopman; Rosa Rademakers; Afina W. Lemstra; Yolande A.L. Pijnenburg; Philip Scheltens; Thomas Gasser; Patrick F. Chinnery; Bernhard Hemmer; Martijn A. Huisman; Juan Troncoso; Fermin Moreno; Ellen A. Nohr; Thorkild I.A. Sørensen; Peter Heutink; Pascual Sánchez-Juan; Danielle Posthuma; G. Coppola; A. M. Karydas; A. Varpetian; T. M. Foroud; A. I. Levey; W. A. Kukull; M. F. Mendez; J. Ringman

doi: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

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, Daniel Alcolea, Heinz Wiendl, Samantha L. Strickland, Pau Pastor, Eloy Rodríguez Rodríguez, Bradley F. Boeve, Ronald C. Petersen, Tanis J. Ferman, Jay A. van Gerpen, Marcel J.T. Reinders, Ryan J. Uitti, Lluís Tárraga, Wolfgang Maier, Oriol Dols-Icardo, Amit Kawalia, Maria Carolina Dalmasso, Mercè Boada, Uwe K. Zettl, Natasja M. van Schoor, Marian Beekman, Mariet Allen, Eliezer Masliah, Adolfo López de Munain, Alexander Pantelyat, Zbigniew K. Wszolek, Owen A. Ross, Dennis W. Dickson, Neill R. Graff-Radford, David Knopman, Rosa Rademakers, Afina W. Lemstra, Yolande A.L. Pijnenburg, Philip Scheltens, Thomas Gasser, Patrick F. Chinnery, Bernhard Hemmer, Martijn A. Huisman, Juan Troncoso, Fermin Moreno, Ellen A. Nohr, Thorkild I.A. Sørensen, Peter Heutink, Pascual Sánchez-Juan, Danielle Posthuma, G. Coppola, A. M. Karydas, A. Varpetian, T. M. Foroud, A. I. Levey, W. A. Kukull, M. F. Mendez, J. Ringman

Departamento de Medicina

Hospital Universitario Donostia

Producción científica: Contribución a una revista › Artículo › Investigación

73 Citas (Scopus)

Resumen

© 2019, The Author(s). 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.

Idioma original	Inglés
Páginas (desde-hasta)	237-250
Número de páginas	14
Publicación	Acta Neuropathologica
Volumen	138
N.º	2
DOI	https://doi.org/10.1007/s00401-019-02026-8
Estado	Publicada - 1 ago 2019

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10.1007/s00401-019-02026-8

https://ddd.uab.cat/record/226469

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http://www.mendeley.com/research/nonsynonymous-mutation-plcg2-reduces-risk-alzheimers-disease-dementia-lewy-bodies-frontotemporal-dem

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van der Lee, S. J., Conway, O. J., Jansen, I., Carrasquillo, M. M., Kleineidam, L., van den Akker, E., Hernández, I., van Eijk, K. R., Stringa, N., Chen, J. A., Zettergren, A., Andlauer, T. F. M., Diez-Fairen, M., Simon-Sanchez, J., Lleó, A., Zetterberg, H., Nygaard, M., Blauwendraat, C., Savage, J. E., ... Ringman, J. (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, 138(2), 237-250. https://doi.org/10.1007/s00401-019-02026-8

@article{dc2c2b14246d4529b9cae3730b2dc8d8,

title = "A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer{\textquoteright}s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity",

abstract = "{\textcopyright} 2019, The Author(s). The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer{\textquoteright}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{\textquoteright}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.",

keywords = "ACTIVATION, APOE, AUTOIMMUNITY, Alzheimer's disease, Alzheimer{\textquoteright}s disease, Amyotrophic lateral sclerosis, Dementia with Lewy bodies, Frontotemporal dementia, GENETIC ARCHITECTURE, GENOME-WIDE ASSOCIATION, INFLAMMATION, INNATE IMMUNITY, Longevity, MECHANISMS, Multiple sclerosis, Neurodegenerative disease, PHOSPHOLIPASE-C-GAMMA, PLCG2, Parkinson's disease, Parkinson{\textquoteright}s disease, Phospholipase C Gamma 2, Progressive supranuclear palsy, REPLICATION",

author = "{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 Adelina Orellana and {Then Bergh}, Florian and Xue Wang and Marc Hulsman and Nina Beker and Niccolo Tesi and Morris, {Christopher M.} and Bego{\~n}a Indakoetxea and Collij, {Lyduine E.} and Martin Scherer and Estrella Morenas-Rodr{\'i}guez and Ironside, {James W.} and {van Berckel}, {Bart N.M.} and Daniel Alcolea and Heinz Wiendl and Strickland, {Samantha L.} and Pau Pastor and {Rodr{\'i}guez Rodr{\'i}guez}, Eloy and Boeve, {Bradley F.} and Petersen, {Ronald C.} and Ferman, {Tanis J.} and {van Gerpen}, {Jay A.} and Reinders, {Marcel J.T.} and Uitti, {Ryan J.} and Llu{\'i}s T{\'a}rraga and Wolfgang Maier and Oriol Dols-Icardo and Amit Kawalia and Dalmasso, {Maria Carolina} and Merc{\`e} Boada and Zettl, {Uwe K.} and {van Schoor}, {Natasja M.} and Marian Beekman and Mariet Allen and Eliezer Masliah and {de Munain}, {Adolfo L{\'o}pez} and Alexander Pantelyat and Wszolek, {Zbigniew K.} and Ross, {Owen A.} and Dickson, {Dennis W.} and Graff-Radford, {Neill R.} and David Knopman and Rosa Rademakers and Lemstra, {Afina W.} and Pijnenburg, {Yolande A.L.} and Philip Scheltens and Thomas Gasser and Chinnery, {Patrick F.} and Bernhard Hemmer and Huisman, {Martijn A.} and Juan Troncoso and Fermin Moreno and Nohr, {Ellen A.} and S{\o}rensen, {Thorkild I.A.} and Peter Heutink and Pascual S{\'a}nchez-Juan and Danielle Posthuma and G. Coppola and Karydas, {A. M.} and A. Varpetian and Foroud, {T. M.} and Levey, {A. I.} and Kukull, {W. A.} and Mendez, {M. F.} and J. Ringman",

year = "2019",

month = aug,

day = "1",

doi = "10.1007/s00401-019-02026-8",

language = "English",

volume = "138",

pages = "237--250",

number = "2",

}

van der Lee, SJ, Conway, OJ, Jansen, I, Carrasquillo, MM, Kleineidam, L, van den Akker, E, Hernández, I, van Eijk, KR, Stringa, N, Chen, JA, Zettergren, A, Andlauer, TFM, Diez-Fairen, M, Simon-Sanchez, J, Lleó, A, Zetterberg, H, Nygaard, M, Blauwendraat, C, Savage, JE, Mengel-From, J, Moreno-Grau, S, Wagner, M, Fortea, J, Keogh, MJ, Blennow, K, Skoog, I, Friese, MA, Pletnikova, O, Zulaica, M, Lage, C, de Rojas, I, Riedel-Heller, S, Illán-Gala, I, Wei, W, Jeune, B, Orellana, A, Then Bergh, F, Wang, X, Hulsman, M, Beker, N, Tesi, N, Morris, CM, Indakoetxea, B, Collij, LE, Scherer, M, Morenas-Rodríguez, E, Ironside, JW, van Berckel, BNM, Alcolea, D, Wiendl, H, Strickland, SL, Pastor, P, Rodríguez Rodríguez, E, Boeve, BF, Petersen, RC, Ferman, TJ, van Gerpen, JA, Reinders, MJT, Uitti, RJ, Tárraga, L, Maier, W, Dols-Icardo, O, Kawalia, A, Dalmasso, MC, Boada, M, Zettl, UK, van Schoor, NM, Beekman, M, Allen, M, Masliah, E, de Munain, AL, Pantelyat, A, Wszolek, ZK, Ross, OA, Dickson, DW, Graff-Radford, NR, Knopman, D, Rademakers, R, Lemstra, AW, Pijnenburg, YAL, Scheltens, P, Gasser, T, Chinnery, PF, Hemmer, B, Huisman, MA, Troncoso, J, Moreno, F, Nohr, EA, Sørensen, TIA, Heutink, P, Sánchez-Juan, P, Posthuma, D, Coppola, G, Karydas, AM, Varpetian, A, Foroud, TM, Levey, AI, Kukull, WA, Mendez, MF & Ringman, J 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, vol. 138, n.º 2, pp. 237-250. 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. / van der Lee, Sven J.; Conway, Olivia J.; Jansen, Iris et al.
En: Acta Neuropathologica, Vol. 138, N.º 2, 01.08.2019, p. 237-250.

Producción científica: Contribución a una revista › Artículo › Investigación

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 - Coppola, G.

AU - Karydas, A. M.

AU - Varpetian, A.

AU - Foroud, T. M.

AU - Levey, A. I.

AU - Kukull, W. A.

AU - Mendez, M. F.

AU - Ringman, J.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - © 2019, The Author(s). 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 - © 2019, The Author(s). 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 - ACTIVATION

KW - APOE

KW - AUTOIMMUNITY

KW - Alzheimer's disease

KW - Alzheimer’s disease

KW - Amyotrophic lateral sclerosis

KW - Dementia with Lewy bodies

KW - Frontotemporal dementia

KW - GENETIC ARCHITECTURE

KW - GENOME-WIDE ASSOCIATION

KW - INFLAMMATION

KW - INNATE IMMUNITY

KW - Longevity

KW - MECHANISMS

KW - Multiple sclerosis

KW - Neurodegenerative disease

KW - PHOSPHOLIPASE-C-GAMMA

KW - PLCG2

KW - Parkinson's disease

KW - Parkinson’s disease

KW - Phospholipase C Gamma 2

KW - Progressive supranuclear palsy

KW - REPLICATION

UR - http://www.mendeley.com/research/nonsynonymous-mutation-plcg2-reduces-risk-alzheimers-disease-dementia-lewy-bodies-frontotemporal-dem

U2 - 10.1007/s00401-019-02026-8

DO - 10.1007/s00401-019-02026-8

M3 - Article

C2 - 31131421

SN - 0001-6322

VL - 138

SP - 237

EP - 250

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 2

ER -

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

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