PLCG2 as a Risk Factor for Alzheimer's Disease.
Open accessAbstract
Background Alzheimer's disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Indeed, genetic variants in microglial genes are linked to risk for late-onset AD (LOAD). Phospholipase C 𝛾 2 (PLCG2) participates in the transduction of signals emanating from immune cell-surface receptors that regulate the inflammatory response and is selectively expressed by microglia in the brain. A rare variant in PLCG2 (P522R) was previously found to be protective against LOAD. Here, we performed association analysis to identify a new genetic variation in PLCG2 that is associated with elevated risk for LOAD. Methods Using whole genome sequencing (N=1,894) and RNA-Seq (N=1,077) data from the AMP-AD cohort, we investigated whether a missense variant in PLCG2 (M28L) was associated with risk for LOAD. We have examined the homology model and space-filling model of PLCG2 generated with PyMOL to investigate the protein structure of PLCG2 with substitutions of LOAD risk and protective variants in PLCG2 . Gene expression analysis and expression quantitative trait loci (eQTL) of PLCG2 were conducted. We also evaluated the relationship between PLCG2 expression levels and amyloid plaque density and expression levels of microglia specific markers ( AIF1 and TMEM119 ). Age, sex, and APOE ε4 carrier status were used as covariates. Finally, we investigated the longitudinal changes PLCG2 expression in the 5XFAD mouse model of AD and it relationship to amyloid pathology progression. Results A rare missense variant in PLCG2 (M28L) confers increased AD risk ( p =0.047; OR=1.164 [95% CI=1.002-1.351]). PLCG2 is highly expressed in the brain and was significantly up-regulated in the parahippocampal gyrus, superior temporal gyrus, and inferior temporal gyrus in LOAD. Higher PLCG2 expression levels were associated with increased brain amyloid deposition. The findings were validated in 5xFAD mice, showing a disease progression-dependent increase in Plcg2 expression with amyloid pathology. Furthermore, eQTL analysis identified several variants as associated with increased PLCG2 expression levels in the brain and other organs. Conclusions Our results provide further evidence that PLCG2 and the M28L variant confers increase risk for LOAD and may play an important role in AD pathophysiology.
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PLCG2 polymorphisms are associated with both reduced and increased risk of Alzheimer's disease and with longevity.
“PLCG2 polymorphisms are associated with both reduced and increased risk of Alzheimer’s disease (AD) and with longevity.”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [8]
The Discussion reports that different PLCG2 variants may increase or reduce late-onset Alzheimer’s disease risk, and the Abstract identifies M28L as an increased-risk variant. Longevity appears only in the title of another study listed in the References; this paper does not itself report or discuss a longevity association. (LLM, conf=0.87)
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Cites
limma powers differential expression analyses for RNA-sequencing and microarray studies
Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv007 · Cited by 40,458 · see citing works
Fast and accurate long-read alignment with Burrows-Wheeler transform.
Li, H., & Durbin, R. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp698 · Cited by 12,063 · see citing works
A framework for variation discovery and genotyping using next-generation DNA sequencing data
DePristo, M. A., Banks, E., Poplin, R. E., Garimella, K. V., Maguire, J., Hartl, C., Philippakis, A., del Angel, G., Rivas, M. A., Hanna, M., et al. (2011) · Nature Genetics · doi:10.1038/ng.806 · Cited by 11,216 · see citing works
LocusZoom: regional visualization of genome-wide association scan results
Pruim, R. J., Welch, R. P., Sanna, S., Teslovich, T. M., Chines, P. S., Gliedt, T. P., Boehnke, M., Abecasis, G. R., & Willer, C. J. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq419 · Cited by 2,707 · see citing works
Ward, L. D., & Kellis, M. (2012) · Nucleic Acids Research · doi:10.1093/nar/gkr917 · Cited by 2,229 · see citing works
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
Karch, C. M., & Goate, A. M. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.05.006 · Cited by 1,357 · see citing works
Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
Woyach, J. A., Furman, R. R., Liu, T.-M., Ozer, H. G., Zapatka, M., Ruppert, A. S., Xue, L., Li, D. H.-H., Steggerda, S. M., Versele, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1400029 · Cited by 1,275 · see citing works
Religious Orders Study and Rush Memory and Aging Project
Bennett, D. A., Buchman, A. S., Boyle, P. A., Barnes, L. L., Wilson, R. S., & Schneider, J. A. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179939 · Cited by 1,260 · see citing works
ARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,126 · see citing works
Age, APOE and sex: triad of risk of Alzheimer’s disease.
Riedel, B. C., Thompson, P. M., & Brinton, R. D. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.03.012 · Cited by 627 · see citing works
A multi-omic atlas of the human frontal cortex for aging and Alzheimer’s disease research
De Jager, P. L., Ma, Y., McCabe, C., Xu, J., Vardarajan, B. N., Felsky, D., Klein, H.-U., White, C. C., Peters, M. A., Lodgson, B., et al. (2018) · Scientific Data · doi:10.1038/sdata.2018.142 · Cited by 598 · see citing works
Hopperton, K. E., Mohammad, D., Trépanier, M. O., Giuliano, V, & Bazinet, R. P. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.246 · Cited by 567 · see citing works
Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk
Efthymiou, A. G., & Goate, A. M. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0184-x · Cited by 562 · see citing works
Activation of phospholipase Cγ by PI 3‐kinase‐induced PH domain‐mediated membrane targeting
Falasca, M., Logan, S. K., Lehto, V. P., Baccante, G., Lemmon, M. A., & Schlessinger, J. (1998) · The EMBO Journal · doi:10.1093/emboj/17.2.414 · Cited by 557 · see citing works
Dementia incidence continues to increase with age in the oldest old: The 90+ study
Corrada, M. M., Brookmeyer, R., Paganini‐Hill, A., Berlau, D., & Kawas, C. H. (2010) · Annals of Neurology · doi:10.1002/ana.21915 · Cited by 523 · see citing works
Wang, M., Beckmann, N. D., Roussos, P., Wang, E., Zhou, X., Wang, Q., Ming, C., Neff, R., Ma, W., Fullard, J. F., et al. (2018) · Scientific Data · doi:10.1038/sdata.2018.185 · Cited by 502 · see citing works
Reiman, E. M., Arboleda-Velasquez, J. F., Quiroz, Y. T., Huentelman, M. J., Beach, T. G., Caselli, R. J., Chen, Y., Su, Y., Myers, A. J., Hardy, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14279-8 · Cited by 473 · see citing works
Allen, M., Carrasquillo, M. M., Funk, C., Heavner, B. D., Zou, F., Younkin, C. S., Burgess, J. D., Chai, H.-S., Crook, J., Eddy, J. A., et al. (2016) · Scientific Data · doi:10.1038/sdata.2016.89 · Cited by 439 · see citing works
TMEM119 marks a subset of microglia in the human brain
Satoh, J., Kino, Y., Asahina, N., Takitani, M., Miyoshi, J., Ishida, T., & Saito, Y. (2016) · Neuropathology · doi:10.1111/neup.12235 · Cited by 434 · see citing works
TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1
Peng, Q., Malhotra, S., Torchia, J. A., Kerr, W. G., Coggeshall, K. M., & Humphrey, M. B. (2010) · Science Signaling · doi:10.1126/scisignal.2000500 · Cited by 413 · see citing works
Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease
Carrasquillo, M. M., Zou, F., Pankratz, V. S., Wilcox, S. L., Ma, L., Walker, L. P., Younkin, S. G., Younkin, C. S., Younkin, L. H., Bisceglio, G. D., et al. (2009) · Nature Genetics · doi:10.1038/ng.305 · Cited by 296 · see citing works
Tmem119-EGFP and Tmem119-CreERT2 Transgenic Mice for Labeling and Manipulating Microglia
Kaiser, T., & Feng, G. (2019) · eneuro · doi:10.1523/eneuro.0448-18.2019 · Cited by 259 · see citing works
Castillo, E., Leon, J., Mazzei, G., Abolhassani, N., Haruyama, N., Saito, T., Saido, T., Hokama, M., Iwaki, T., Ohara, T., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-17999-3 · Cited by 158 · see citing works
Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
Magno, L., Lessard, C. B., Martins, M., Lang, V., Cruz, P., Asi, Y., Katan, M., Bilsland, J., Lashley, T., Chakrabarty, P., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0469-0 · Cited by 143 · see citing works
DESGESCO (Dementia Genetics Spanish Consortium), E. (. D. E. D. B., van der Lee, S. J., biobank), E. (. D. E. D., IFGC (International FTD-Genomics Consortium), I. (. I. P. D. G. C., IPDGC (The International Parkinson Disease Genomics Consortium), Dementia), R.-F. (. A. M. F. I. F.-T., (NBB), N. B. B., The GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Conway, O. J., Jansen, I., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02026-8 · Cited by 120 · see citing works
VarSite: Disease variants and protein structure
Laskowski, R. A., Stephenson, J. D., Sillitoe, I., Orengo, C. A., & Thornton, J. M. (2019) · Protein Science · doi:10.1002/pro.3746 · Cited by 117 · see citing works
Conway, O. J., Carrasquillo, M. M., Wang, X., Bredenberg, J. M., Reddy, J. S., Strickland, S. L., Younkin, C. S., Burgess, J. D., Allen, M., Lincoln, S. J., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0289-x · Cited by 112 · see citing works
Keaney, J., Gasser, J., Gillet, G., Scholz, D., & Kadiu, I. (2019) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-019-09839-0 · Cited by 98 · see citing works
Protein kinase C and phospholipase C: bilayer interactions and regulation
Hurley, J. H., & Grobler, J. A. (1997) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(97)80122-4 · Cited by 68 · see citing works
(ADNI), A. D. N. I., Kleineidam, L., Chouraki, V., Próchnicki, T., van der Lee, S. J., Madrid-Márquez, L., Wagner-Thelen, H., Karaca, I., Weinhold, L., Wolfsgruber, S., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02138-6 · Cited by 62 · see citing works
Hajicek, N., & Sondek, J. (2019) · Worldwide Protein Data Bank · doi:10.2210/pdb6pbc/pdb · Cited by 58 · see citing works
Self-citationDalmasso, M. C., Brusco, L. I., Olivar, N., Muchnik, C., Hanses, C., Milz, E., Becker, J., Heilmann-Heimbach, S., Hoffmann, P., Prestia, F. A., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0394-9 · Cited by 51 · see citing works
Comparison of multi-sample variant calling methods for whole genome sequencing
Nho, K. T., West, J. D., Li, H., Henschel, R., Tavares, M. C., Sanjay, A. B., Weiner, M. W., Green, R. C., Toga, A. W., & Saykin, A. J. (2014) · IEEE International Conference on Systems Biology · doi:10.1109/isb.2014.6990432 · Cited by 18 · see citing works
Self-citationCold Urticaria, Immunodeficiency, and Autoimmunity Related to PLCG2 Deletions
Smart, B. A. (2012) · PEDIATRICS · doi:10.1542/peds.2012-2183jj · Cited by 17 · see citing works
Auto-inhibition and phosphorylation-induced activation of PLC-gamma isozymes
Hajicek, N., & Sondek, J. (2013) · Worldwide Protein Data Bank · doi:10.2210/pdb4k44/pdb · Cited by 11 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 8
- Isik AT: Late onset Alzheimer's disease in older people. Clin Interv Aging 2010, 5:307-311.
- Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A et al: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet 2019, 51(3):414-430.
- Hernandez D, Egan SE, Yulug IG, Fisher EM: Mapping the gene that encodes phosphatidylinositol-specific phospholipase C-gamma 2 in the human and the mouse. Genomics 1994, 23(2):504-507.
- Walliser C, Hermkes E, Schade A, Wiese S, Deinzer J, Zapatka M, Desire L, Mertens D, Stilgenbauer S, Gierschik P: The Phospholipase Cgamma2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein. J Biol Chem 2016, 291(42):22136- 22148.
- Morris JC: The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993, 43(11):2412-2414.
- Hajicek N, Charpentier TH, Rush JR, Harden TK, Sondek J: Autoinhibition and phosphorylation-induced activation of phospholipase C-gamma isozymes. Biochemistry 2013, 52(28):4810-4819.
- Matsuda M, Paterson HF, Rodriguez R, Fensome AC, Ellis MV, Swann K, Katan M: Real time fluorescence imaging of PLC gamma translocation and its interaction with the epidermal growth factor receptor. J Cell Biol 2001, 153(3):599-612.
- Everett KL, Bunney TD, Yoon Y, Rodrigues-Lima F, Harris R, Driscoll PC, Abe K, Fuchs H, de Angelis MH, Yu P et al: Characterization of phospholipase C gamma enzymes with gain-of-function mutations. J Biol Chem 2009, 284(34):23083-23093.
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Seto, M., Weiner, R. L., Dumitrescu, L., & Hohman, T. J. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00452-5 · Cited by 135 · see citing works
Tsai, A. P., Lin, P. B.-C., Dong, C., Moutinho, M., Casali, B. T., Liu, Y., Lamb, B. T., Landreth, G. E., Oblak, A. L., & Nho, K. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105303 · Cited by 104 · see citing works
Self-citationVariant TREM2 Signaling in Alzheimer's Disease
Olufunmilayo, E. O., & Holsinger, R. M. D. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167470 · Cited by 32 · see citing works
Li, H., Initiative, F. T. A. D. N., Liu, H., Lutz, M. W., & Luo, S. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-220680 · Cited by 17 · see citing works
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Yamada, S. M., & Pontillo, A. (2022) · Molecular Immunology · doi:10.1016/j.molimm.2022.03.005 · Cited by 13 · see citing works
Apiraksattayakul, S., Pingaew, R., Prachayasittikul, V., Ruankham, W., Tantimongcolwat, T., Prachayasittikul, V., Prachayasittikul, S., & Phopin, K. (2024) · Neurochemical Research · doi:10.1007/s11064-024-04281-y · Cited by 10 · see citing works
Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain
Hopp, S. C., Rogers, J. G., Smith, S., Campos, G., Miller, H., Barannikov, S., Kuri, E. G., Wang, H., Han, X., Bieniek, K. F., et al. (2023) · doi:10.1101/2023.12.06.570499 · Cited by 4 · see citing works
- Authors
- Tsai, A. P., Dong, C., Preuss, C., Moutinho, M., Lin, P. B.-C., Hajicek, N., Sondek, J., Bissel, S. J., Oblak, A. L., Carter, G. W., Liu, Y., Landreth, G. E., Lamb, B. T., & Nho, K.
- Affiliations
- Stark Neurosciences Research Institute
- Indiana University School of Medicine (US)
- Jackson Laboratory (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Nho, Kwangsik
- ORCID
- Publisher
- Research Square Platform LLC
- Published
- 2020-06-30
- OpenAlex
- W4255861615
- Cited by
- 7
- References
- 36
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 3 · 2021: 2
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Funders
- Emory University
- National Institutes of Health (AG054345)
- National Institute on Aging (AG054345, AG050597, AG063250, RF1AG051495, NLM R01 LM012535, R03AG063250, AG051495, RF1AG050597, U54AG054345)
- National Institute of General Medical Sciences (R01GM057391)
- U.S. National Library of Medicine (R01LM012535)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, PLCγ2, late-onset Alzheimer's disease, genetic risk factors, microglia, amyloid plaques, expression quantitative trait loci, 5xFAD mice, amyloid pathology, AIF1, TMEM119, parahippocampal gyrus
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