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Acta Neuropathol. 2019 May 27. doi: 10.1007/s00401-019-02026-8. [Epub ahead of print]

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 SJ1,2, Conway OJ3, Jansen I4,5, Carrasquillo MM3, Kleineidam L6,7,8, van den Akker E9,10, Hernández I11,12, van Eijk KR13, Stringa N14, Chen JA15, Zettergren A16, Andlauer TFM17,18,19, Diez-Fairen M20,21, Simon-Sanchez J22,23, Lleó A12,24, Zetterberg H25,26,27, Nygaard M28, Blauwendraat C29, Savage JE5, Mengel-From J30, Moreno-Grau S11, Wagner M6,7, Fortea J12,24, Keogh MJ31,32, Blennow K25,26, Skoog I16, Friese MA19,33, Pletnikova O34, Zulaica M12,35, Lage C12,36,37, de Rojas I11,12, Riedel-Heller S38, Illán-Gala I12,24, Wei W32, Jeune B30, Orellana A11,12, Then Bergh F19,39, Wang X3, Hulsman M4,40,10, Beker N4, Tesi N4,40,10, Morris CM41, Indakoetxea B12,35,42, Collij LE43, Scherer M44, Morenas-Rodríguez E12,24, Ironside JW45, van Berckel BNM43, Alcolea D12,24, Wiendl H19,46, Strickland SL3, Pastor P20,21, Rodríguez Rodríguez E12,36,37; DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank); EADB (Alzheimer Disease European DNA biobank); IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium); IPDGC (The International Parkinson Disease Genomics Consortium); RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia); Netherlands Brain Bank (NBB), Boeve BF47, Petersen RC47, Ferman TJ48, van Gerpen JA49, Reinders MJT50, Uitti RJ49, Tárraga L11,12, Maier W6,7, Dols-Icardo O12,24, Kawalia A8, Dalmasso MC8,51, Boada M11,12, Zettl UK19,52, van Schoor NM14, Beekman M9, Allen M3, Masliah E53, de Munain AL12,35,54, Pantelyat A55, Wszolek ZK49, Ross OA3, Dickson DW3, Graff-Radford NR49, Knopman D47, Rademakers R3, Lemstra AW4, Pijnenburg YAL4, Scheltens P4, Gasser T56, Chinnery PF32,57, Hemmer B18,19,58, Huisman MA14,59, Troncoso J34, Moreno F12,35,42, Nohr EA60, Sørensen TIA61,62,63, Heutink P22,23, Sánchez-Juan P12,36,37, Posthuma D40,5; GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Clarimón J12,24, Christensen K28,64,65, Ertekin-Taner N3,49, Scholz SW29,55, Ramirez A6,8, Ruiz A11,12, Slagboom E9,66, van der Flier WM4, Holstege H67,68.

Author information

1
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. s.j.vanderlee@amsterdamumc.nl.
2
Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. s.j.vanderlee@amsterdamumc.nl.
3
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, 32224, USA.
4
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
5
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
6
Department for Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany.
7
DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany.
8
Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine, University Hospital Cologne, Cologne, Germany.
9
Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
10
Pattern Recognition and Bioinformatics, Delft University of Technology, Delft, The Netherlands.
11
Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.
12
Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
13
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
14
Amsterdam UMC-Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
15
Interdepartmental Program in Bioinformatics, University of California, Los Angeles, USA.
16
Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AgeCap) at the University of Gothenburg, Gothenburg, Sweden.
17
Max Planck Institute of Psychiatry, Munich, Germany.
18
Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
19
German Competence Network Multiple Sclerosis (KKNMS), Munich, Germany.
20
Movement Disorders and Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain.
21
Fundacio per la Recerca Biomedica I Social Mutua Terrassa, Terrassa, Barcelona, Spain.
22
German Center for Neurodegenerative Diseases (DZNE)-Tübingen, Tübingen, Germany.
23
Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
24
Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.
25
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
26
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
27
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
28
The Danish Aging Research Center, Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.
29
Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, 20892-3707, USA.
30
Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.
31
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
32
Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK.
33
Institut für Neuroimmunologie und Multiple Sklerose (INIMS), Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
34
Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA.
35
Instituto Biodonostia, San Sebastian, Spain.
36
University Hospital "Marques de Valdecilla", Santander, Spain.
37
IDIVAL, Santander, Spain.
38
Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Leipzig, Germany.
39
Department of Neurology, University of Leipzig, Leipzig, Germany.
40
Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
41
Newcastle Brain Tissue Resource, Edwardson Building, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
42
Cognitive Disorders Unit, Department of Neurology, Hospital Universitario San Sebastian, San Sebastian, Spain.
43
Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
44
Department of Primary Medical Care, Center for Psychosocial Medicine, University Medical Center, Hamburg-Eppendorf, Germany.
45
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH4 2XU, UK.
46
Department of Neurology, Klinik für Neurologie mit Institut für Translationale Neurologie, University of Münster, Münster, Germany.
47
Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, 55905, USA.
48
Department of Psychiatry and Psychology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA.
49
Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA.
50
Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands.
51
Fundación Instituto Leloir-IIBBA-CONICET, Buenos Aires, Argentina.
52
Department of Neurology, University of Rostock, Rostock, Germany.
53
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
54
Department of Neurology, Hospital Universitario San Sebastian, San Sebastian, Spain.
55
Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, 21287, USA.
56
Center of Neurology, Department of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
57
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK.
58
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
59
Department of Sociology, VU University, Amsterdam, The Netherlands.
60
Research Unit of Gynecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
61
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Copenhagen, Denmark.
62
Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
63
MRC Integrative Epidemiology Unit, Bristol University, Bristol, UK.
64
Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
65
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
66
Dutch Society for Research on Ageing, Leiden, The Netherlands.
67
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. h.holstege@amsterdamumc.nl.
68
Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. h.holstege@amsterdamumc.nl.

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.

KEYWORDS:

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

PMID:
31131421
DOI:
10.1007/s00401-019-02026-8

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