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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
University of California, Los Angeles (UCLA) - Department of Neurology; University of California, Los Angeles (UCLA) - Department of Psychiatry and Biobehavioral Sciences
University of Cologne - Division of Neurogenetics and Molecular Psychiatry; University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry
Background: PLCG2 plays an important role in immune system signaling, and is expressed in several immune cell types including microglia in the brain. In 2017, the genetic variant rs72824905 (p.Pro522Arg) in the PLCG2 gene (Phospholipase C Gamma 2) was associated with a reduced risk of Alzheimer's disease (AD). Here we investigated whether the rs72824905 variant had a similar protective effect on six other brain diseases. We further tested if rs72824905 increases the likelihood of longevity, since a reduced risk of neurodegenerative diseases might associate with general survival.
Methods: We investigated the effect of carrying rs72824905 on disease risk in a total of 53,627 patients with one of seven brain diseases. We studied AD (N = 4,985), frontotemporal dementia (FTD) (N = 2,437), dementia with Lewy-bodies (DLB) (N = 1,446), progressive supranuclear palsy (PSP) (N = 882), Parkinson's disease (PD) (N = 28,448) amyotrophic lateral sclerosis (ALS) (N = 10,953) and multiple sclerosis (MS) (N = 4,476) by comparing them with in total 149,290 controls using logistic regression models. Next, we studied the effect of carrying rs72824905 on longevity by comparing individuals who reached at least 90 years (N = 3,516) with individuals who died before age 90 years or were last screened before 90 years (N = 9,677). In addition, we studied the association of rs72824905 with survival after the age of 90 in a subset of long-lived individuals followed until death. Finally, we supported our findings by studying by-proxy phenotypes in the ~450.000 participants of the UK Biobank. We associated the rs72824905 genotypes of UK Biobank participants with parental history of dementia as proxy for dementia and as a proxy for longevity we studied parental age over 90 as well as parental age over 95 years of age. All individuals were of European ancestry.
Results: The rs72824905-G allele associated with a reduced AD risk (Odds ratio (OR) = 0·57, p = 4·7×10-4), a reduced DLB risk (OR = 0·54, p = 4·5×10-2) and reduced FTD risk (OR = 0·61, p = 1·0×10 2). We did not find evidence for association of rs72824905 with the risks of PSP (OR = 1·46, p = 0·19), PD (OR = 1·18, p = 0·10), ALS (OR = 1·07, p = 0·26) or MS (OR = 0·99, p = 0·95). The rs72824905-G allele was associated with a 1·49 increased likelihood of reaching >90 years (p = 6.4×10-3): variant carriers lived longer after the age of 90 years, median 4.7 (inter quartile range = 1·9 - 7·4) years compared to non-carriers 3.3 (IQR = 1·4 - 5·8) (Hazard ratio = 0·75, p = 0·07). By-proxy analyses supported the associations of rs728824905 with dementia as well as longevity. Variant carriers had a lower likelihood of having a parent with dementia (OR = 0·88, p = 1·8×10 3) and had a significantly increased likelihood of having a parent aged >95 years (OR = 1·19, p = 2·1×10-2).
Conclusions: Our results show that rs72824905 in PLCG2 protects from AD, DLB and FTD and increases the likelihood of longevity. Together, our findings highlight a central role for PLCG2 related immune signaling in the brain, which should be the subject of future studies as a drug target for multiple brain diseases.
Funding Statement: The authors present a short description of 16 cohorts, often including multiple sites or studies, that contributed to this manuscript and their funding sources in Supplementary Table 1: Amsterdam dementia Cohort (ADC), 100-Plus study, German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe), Brain compendium, Clinical AD, Sweden, Danish data, Fundació ACE (FACE), Genetics of Healthy Ageing Study (GEHA – NL), Gothenburg Birth Cohort (GBC) Studies, International FTD-Genomics Consortium (IFGC), Kompetenznetz Multiple Sklerose (KKNMS), Longitudinal Aging Study Amsterdam (LASA), Leiden Longevity Study, Maria Carolina Dalmasso, Mayo Clinic AD, DLB, PD, PSP, NDRU cohort, Oviedo, Pascual Sánchez-Juan, Project MinE, Risk and modifying factors in Fronto Temporal Dementia (RiMoD-FTD): follows The SPIN cohort, San Sebastian, UK Biobank analysis, IPDGC (The International Parkinson Disease Genomics Consortium).
Declaration of Interests: The authors declare no competing interest related to this work.
Ethics Approval Statement: Studies were approved by corresponding ethics committees and informed consent was obtained for all participants.
van der Lee, Sven J. and Conway, Olivia J. and Jansen, Iris and Carrasquillo, Minerva M. and Kleineidam, Luca and Akker, Erik van den and Hernández, Isabel and Van Eijk, Kristel R. and Stringa, Najada and Chen, Jason A. and Zettergren, Anna and Andlauer, Till F. M. and Diez-Fairen, Monica and Simon-Sanchez, Javier and Lleó, Alberto and Zetterberg, Henrik and Nygaard, Marianne and Blauwendraat, Cornelis and Savage, Jeanne E. and Mengel-From, Jonas and Moreno-Grau, Sonia and Wagner, Michael and Fortea, Juan and Keogh, Michael J. and Blennow, Kaj and Skoog, Ingmar and Friese, Manuel A. and Pletnikova, Olga and Zulaica, Miren and Lage, Carmen and de Rojas, Itziar and Riedel-Heller, Steffi and Illán-Gala, Ignacio and Wei, Wei and Jeune, Bernard and Orellana, Adela and Bergh, Florian Then and Wang, Xue and Hulsman, Marc and Beker, Nina and Tesí, Niccolo and Morris, Christopher and Indakoetxea, Begoña and Collij, Lyduine E. and Scherer, Martin and Morenas-Rodríguez, Estrella and Ironside, James W. and Berckel, Bart. N.M. van and Alcolea, Daniel and Wiendl, Heinz and Strickland, Samantha L. and Pastor, Pau and Rodríguez, Eloy Rodríguez and Consortium, DESGESCO Dementia Genetics Spanish and Biobank, Alzheimer Disease European DNA and Consortium, IFGC International FTD-Genomics and Consortium, IPDGC The International Parkinson Disease Genomics and Dementia, RiMod-FTD Rsk and Modifying factors in Fronto-Temporal and Bank (NBB), Netherlands Brain and Boeve, Bradley F. and Petersen, Ronald C. and Ferman, Tanis J. and Gerpen, Jay A. van and Reinders, Marcel J. T. and Uitti, Ryan J. and Tarraga, Lluis and Maier, Wolfgang and Dols-Icardo, Oriol and Kawalia, Amit and Dalmasso, Maria Carolina and Boada, Mercè and Zettl, Uwe K. and van Schoor, Natasja M. and Beekman, Marian and Allen, Mariet and Masliah, Eliezer and Munain, Adolfo López de and Pantelyat, Alexander and Wszolek, Zbigniew K. and Ross, Owen A. and Dickson, Dennis W. and Graff-Radford, Neill R. and Knopman, David and Rademakers, Rosa and Lemstra, Afina W. and Pijnenburg, Yolande A. L. and Scheltens, Philip and Gasser, Thomas and Chinnery, Patrick F. and Hemmer, Bernhard and Huisman, Martijn A. and Troncoso, Juan and Moreno, Fermin and Nohr, Ellen A. and Sørensen, Thorkild I. A. and Heutink, Peter and Sánchez-Juan, Pascual and Posthuma, Danielle and Coppola, Giovanni and Clarimón, Jordi and Christensen, Kaare and Ertekin-Taner, Nilüfer and Scholz, Sonja W. and Ramirez, Alfredo and Ruiz, Agustin and Slagboom, Eline and van der Flier, Wiesje M. and Holstege, Henne, 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 (December 21, 2018). Available at SSRN: https://ssrn.com/abstract=3307650 or http://dx.doi.org/10.2139/ssrn.3307650
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