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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

Lookup NU author(s): Dr Michael Keogh, Dr Christopher Morris

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Abstract

© 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.


Publication metadata

Author(s): van der Lee SJ, Conway OJ, Jansen I, Carrasquillo MM, Kleineidam L, van den Akker E, Hernandez I, van Eijk KR, Stringa N, Chen JA, Zettergren A, Andlauer TFM, Diez-Fairen M, Simon-Sanchez J, Lleo 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, Illan-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-Rodriguez E, Ironside JW, van Berckel BNM, Alcolea D, Wiendl H, Strickland SL, Pastor P, Rodriguez Rodriguez E, Boeve BF, Petersen RC, Ferman TJ, van Gerpen JA, Reinders MJT, Uitti RJ, Tarraga 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, Sorensen TIA, Heutink P, Sanchez-Juan P, Posthuma D, Coppola G, Karydas AM, Varpetian A, Foroud TM, Levey AI, Kukull WA, Mendez MF, Ringman J, Chui H, Cotman C, DeCarli C, Miller BL, Geschwind DH, Clarimon J, Christensen K, Ertekin-Taner N, Scholz SW, Ramirez A, Ruiz A, Slagboom E, van der Flier WM, Holstege H

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica

Year: 2019

Issue: ePub ahead of Print

Online publication date: 27/05/2019

Acceptance date: 05/05/2019

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer Verlag

URL: https://doi.org/10.1007/s00401-019-02026-8

DOI: 10.1007/s00401-019-02026-8

PubMed id: 31131421


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