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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

      research-article
      1 , 2 , , 3 , 1 , 4 , 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 11 , 23 , 24 , 25 , 26 , 27 , 28 , 4 , 29 , 10 , 5 , 6 , 11 , 23 , 30 , 31 , 24 , 25 , 15 , 18 , 32 , 33 , 11 , 34 , 11 , 35 , 36 , 10 , 11 , 37 , 11 , 23 , 31 , 29 , 10 , 11 , 18 , 38 , 3 , 1 , 2 , 9 , 1 , 1 , 2 , 9 , 39 , 11 , 34 , 40 , 41 , 42 , 11 , 23 , 43 , 41 , 11 , 23 , 18 , 44 , 3 , 19 , 20 , 11 , 35 , 36 , 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), 45 , 45 , 46 , 47 , 64 , 47 , 10 , 11 , 5 , 6 , 11 , 23 , 7 , 7 , 48 , 10 , 11 , 18 , 49 , 13 , 8 , 3 , 50 , 11 , 34 , 51 , 52 , 47 , 3 , 3 , 47 , 45 , 3 , 1 , 1 , 1 , 53 , 31 , 54 , 17 , 18 , 55 , 13 , 56 , 33 , 11 , 34 , 40 , 57 , 58 , 59 , 60 , 21 , 22 , 11 , 35 , 36 , 2 , 4 , The GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, 11 , 23 , 27 , 61 , 62 , 3 , 47 , 28 , 52 , 5 , 7 , 10 , 11 , 8 , 63 , 1 , 1 , 2 ,
      Acta Neuropathologica
      Springer Berlin Heidelberg
      Alzheimer’s disease, Frontotemporal dementia, Dementia with Lewy bodies, Progressive supranuclear palsy, Parkinson’s disease, Amyotrophic lateral sclerosis, Multiple sclerosis, Neurodegenerative disease, Longevity, PLCG2, Phospholipase C Gamma 2

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          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.

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          The online version of this article (10.1007/s00401-019-02026-8) contains supplementary material, which is available to authorized users.

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          Most cited references31

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          Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.

          Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance. We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis. We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell-receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib. Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell-receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.).
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            GWAS on family history of Alzheimer’s disease

            Alzheimer’s disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. We show that self-report of parental history of Alzheimer’s dementia for case ascertainment in a genome-wide association study of 314,278 participants from UK Biobank (27,696 maternal cases, 14,338 paternal cases) is a valid proxy for an AD genetic study. After meta-analysing with published consortium data (n = 74,046 with 25,580 cases across the discovery and replication analyses), three new AD-associated loci (P < 5 × 10−8) are identified. These contain genes relevant for AD and neurodegeneration: ADAM10, BCKDK/KAT8 and ACE. Novel gene-based loci include drug targets such as VKORC1 (warfarin dose). We report evidence that the association of SNPs in the TOMM40 gene with AD is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. However, it is likely that multiple variants are affecting the trait and gene methylation/expression. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, as they contain genes that are drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications.
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              Role of the innate and adaptive immune responses in the course of multiple sclerosis.

              Multiple sclerosis is a chronic disease of the CNS that leads to substantial disability in most patients. The early phase is characterised by relapses and the later phase by progressive disability. Results from immunological, genetic, and histopathological studies and treatment trials have shown that the immune system plays a key part in the disease course. Findings from animal models and immunological studies of patients with multiple sclerosis suggest a change in the involvement of the immune system during disease initiation and progression. These findings suggest that a peripheral immune response targeting the CNS drives the disease process during the early phase, whereas immune reactions within the CNS dominate the progressive phase. These concepts for the differential involvement of immune responses in the early and progressive phase of this disease have important implications for future research in the pathogenesis and treatment of multiple sclerosis.
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                Author and article information

                Contributors
                s.j.vanderlee@amsterdamumc.nl
                h.holstege@amsterdamumc.nl
                Journal
                Acta Neuropathol
                Acta Neuropathol
                Acta Neuropathologica
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0001-6322
                1432-0533
                27 May 2019
                27 May 2019
                2019
                : 138
                : 2
                : 237-250
                Affiliations
                [1 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, , Vrije Universiteit Amsterdam, Amsterdam UMC, ; Amsterdam, The Netherlands
                [2 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Department of Clinical Genetics, , Vrije Universiteit Amsterdam, Amsterdam UMC, ; Amsterdam, The Netherlands
                [3 ]ISNI 0000 0004 0443 9942, GRID grid.417467.7, Department of Neuroscience, , Mayo Clinic Florida, ; Jacksonville, FL 32224 USA
                [4 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, , Vrije Universiteit Amsterdam, Amsterdam UMC, ; Amsterdam, The Netherlands
                [5 ]ISNI 0000 0001 2240 3300, GRID grid.10388.32, Department for Neurodegenerative Diseases and Geriatric Psychiatry, , University of Bonn, ; Bonn, Germany
                [6 ]ISNI 0000 0004 0438 0426, GRID grid.424247.3, DZNE, German Center for Neurodegenerative Diseases, ; Bonn, Germany
                [7 ]ISNI 0000 0000 8852 305X, GRID grid.411097.a, Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine, , University Hospital Cologne, ; Cologne, Germany
                [8 ]ISNI 0000000089452978, GRID grid.10419.3d, Molecular Epidemiology, , Leiden University Medical Center, ; Leiden, The Netherlands
                [9 ]ISNI 0000 0001 2097 4740, GRID grid.5292.c, Pattern Recognition and Bioinformatics, , Delft University of Technology, ; Delft, The Netherlands
                [10 ]ISNI 0000 0001 2325 3084, GRID grid.410675.1, Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, , Universitat Internacional de Catalunya, ; Barcelona, Spain
                [11 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), ; Madrid, Spain
                [12 ]ISNI 0000000090126352, GRID grid.7692.a, Department of Neurology, Brain Center Rudolf Magnus, , University Medical Center Utrecht, ; Utrecht, The Netherlands
                [13 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Amsterdam UMC-Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, , Amsterdam Public Health Research Institute, ; Amsterdam, The Netherlands
                [14 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Interdepartmental Program in Bioinformatics, , University of California, ; Los Angeles, USA
                [15 ]ISNI 0000 0000 9919 9582, GRID grid.8761.8, 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
                [16 ]ISNI 0000 0000 9497 5095, GRID grid.419548.5, Max Planck Institute of Psychiatry, ; Munich, Germany
                [17 ]ISNI 0000000123222966, GRID grid.6936.a, Department of Neurology, Klinikum rechts der Isar, , Technical University of Munich, ; Munich, Germany
                [18 ]GRID grid.491916.2, German Competence Network Multiple Sclerosis (KKNMS), ; Munich, Germany
                [19 ]ISNI 0000 0004 1794 4956, GRID grid.414875.b, Movement Disorders and Memory Unit, Department of Neurology, , University Hospital Mutua de Terrassa, ; Barcelona, Spain
                [20 ]ISNI 0000 0004 1794 4956, GRID grid.414875.b, Fundacio per la Recerca Biomedica I Social Mutua Terrassa, ; Terrassa, Barcelona Spain
                [21 ]German Center for Neurodegenerative Diseases (DZNE)-Tübingen, Tübingen, Germany
                [22 ]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Hertie Institute for Clinical Brain Research, , University of Tübingen, ; Tübingen, Germany
                [23 ]GRID grid.7080.f, Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, , Universitat Autonoma de Barcelona, ; Barcelona, Spain
                [24 ]ISNI 000000009445082X, GRID grid.1649.a, Clinical Neurochemistry Laboratory, , Sahlgrenska University Hospital, ; Mölndal, Sweden
                [25 ]ISNI 0000 0000 9919 9582, GRID grid.8761.8, Department of Psychiatry and Neurochemistry, , Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, ; Gothenburg, Sweden
                [26 ]ISNI 0000000121901201, GRID grid.83440.3b, Department of Molecular Neuroscience, , UCL Institute of Neurology, Queen Square, ; London, UK
                [27 ]ISNI 0000 0001 0728 0170, GRID grid.10825.3e, The Danish Aging Research Center, Epidemiology, Biostatistics and Biodemography, Department of Public Health, , University of Southern Denmark, ; Odense, Denmark
                [28 ]ISNI 0000 0001 2177 357X, GRID grid.416870.c, Neurodegenerative Diseases Research Unit, , National Institute of Neurological Disorders and Stroke, ; Bethesda, MD 20892-3707 USA
                [29 ]ISNI 0000 0001 0728 0170, GRID grid.10825.3e, Epidemiology, Biostatistics and Biodemography, Department of Public Health, , University of Southern Denmark, ; Odense, Denmark
                [30 ]ISNI 0000 0001 0462 7212, GRID grid.1006.7, Institute of Genetic Medicine, Newcastle University, ; Newcastle upon Tyne, NE1 3BZ UK
                [31 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Clinical Neurosciences, , University of Cambridge, ; Cambridge, CB2 0QQ UK
                [32 ]ISNI 0000 0001 2180 3484, GRID grid.13648.38, Institut für Neuroimmunologie und Multiple Sklerose (INIMS), , Universitätsklinikum Hamburg‐Eppendorf, ; Hamburg, Germany
                [33 ]ISNI 0000 0004 0442 9875, GRID grid.411940.9, Department of Pathology (Neuropathology), , Johns Hopkins University Medical Center, ; Baltimore, MD USA
                [34 ]GRID grid.432380.e, Instituto Biodonostia, ; San Sebastian, Spain
                [35 ]ISNI 0000 0001 0627 4262, GRID grid.411325.0, University Hospital “Marques de Valdecilla”, ; Santander, Spain
                [36 ]GRID grid.484299.a, IDIVAL, ; Santander, Spain
                [37 ]ISNI 0000 0001 2230 9752, GRID grid.9647.c, Institute of Social Medicine, Occupational Health and Public Health (ISAP), , University of Leipzig, ; Leipzig, Germany
                [38 ]ISNI 0000 0001 2230 9752, GRID grid.9647.c, Department of Neurology, , University of Leipzig, ; Leipzig, Germany
                [39 ]ISNI 0000 0001 0462 7212, GRID grid.1006.7, Newcastle Brain Tissue Resource, Edwardson Building, Institute of Neuroscience, , Newcastle University, ; Newcastle upon Tyne, NE4 5PL UK
                [40 ]Cognitive Disorders Unit, Department of Neurology, Hospital Universitario San Sebastian, San Sebastian, Spain
                [41 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, , Vrije Universiteit Amsterdam, Amsterdam UMC, ; Amsterdam, The Netherlands
                [42 ]Department of Primary Medical Care, Center for Psychosocial Medicine, University Medical Center, Hamburg-Eppendorf, Germany
                [43 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Centre for Clinical Brain Sciences, , University of Edinburgh, ; Edinburgh, EH4 2XU UK
                [44 ]ISNI 0000 0001 2172 9288, GRID grid.5949.1, Department of Neurology, Klinik für Neurologie mit Institut für Translationale Neurologie, , University of Münster, ; Münster, Germany
                [45 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Department of Neurology, , Mayo Clinic Minnesota, ; Rochester, MN 55905 USA
                [46 ]ISNI 0000 0004 0443 9942, GRID grid.417467.7, Department of Psychiatry and Psychology, , Mayo Clinic Florida, ; Jacksonville, FL 32224 USA
                [47 ]ISNI 0000 0004 0443 9942, GRID grid.417467.7, Department of Neurology, , Mayo Clinic Florida, ; Jacksonville, FL 32224 USA
                [48 ]ISNI 0000 0004 0637 648X, GRID grid.418081.4, Fundación Instituto Leloir-IIBBA-CONICET, ; Buenos Aires, Argentina
                [49 ]ISNI 0000000121858338, GRID grid.10493.3f, Department of Neurology, , University of Rostock, ; Rostock, Germany
                [50 ]ISNI 0000 0000 9372 4913, GRID grid.419475.a, Laboratory of Neurogenetics, , National Institute on Aging, National Institutes of Health, ; Bethesda, MD USA
                [51 ]Department of Neurology, Hospital Universitario San Sebastian, San Sebastian, Spain
                [52 ]ISNI 0000 0004 0442 9875, GRID grid.411940.9, Department of Neurology, , Johns Hopkins University Medical Center, ; Baltimore, MD 21287 USA
                [53 ]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Center of Neurology, Department of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research, , University of Tuebingen, ; Tuebingen, Germany
                [54 ]ISNI 0000000121885934, GRID grid.5335.0, MRC Mitochondrial Biology Unit, , University of Cambridge, ; Cambridge, CB2 0QQ UK
                [55 ]GRID grid.452617.3, Munich Cluster for Systems Neurology (SyNergy), ; Munich, Germany
                [56 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Department of Sociology, , VU University, ; Amsterdam, The Netherlands
                [57 ]ISNI 0000 0001 0728 0170, GRID grid.10825.3e, Research Unit of Gynecology and Obstetrics, Department of Clinical Research, , University of Southern Denmark, ; Odense, Denmark
                [58 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, ; Copenhagen, Denmark
                [59 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, Denmark
                [60 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, MRC Integrative Epidemiology Unit, , Bristol University, ; Bristol, UK
                [61 ]ISNI 0000 0004 0512 5013, GRID grid.7143.1, Clinical Biochemistry and Pharmacology, , Odense University Hospital, ; Odense, Denmark
                [62 ]ISNI 0000 0004 0512 5013, GRID grid.7143.1, Department of Clinical Genetics, , Odense University Hospital, ; Odense, Denmark
                [63 ]Dutch Society for Research on Ageing, Leiden, The Netherlands
                [64 ]ISNI 0000 0001 2097 4740, GRID grid.5292.c, Delft Bioinformatics Lab, , Delft University of Technology, ; Delft, The Netherlands
                Author information
                http://orcid.org/0000-0003-1606-8643
                http://orcid.org/0000-0002-2917-5889
                http://orcid.org/0000-0002-1413-5091
                http://orcid.org/0000-0002-1046-6408
                http://orcid.org/0000-0002-7688-3087
                Article
                2026
                10.1007/s00401-019-02026-8
                6660501
                31131421
                a0ec2f65-d495-4851-b706-70c3228afad2
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 23 March 2019
                : 3 May 2019
                : 5 May 2019
                Categories
                Original Paper
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                © Springer-Verlag GmbH Germany, part of Springer Nature 2019

                Neurology
                alzheimer’s disease,frontotemporal dementia,dementia with lewy bodies,progressive supranuclear palsy,parkinson’s disease,amyotrophic lateral sclerosis,multiple sclerosis,neurodegenerative disease,longevity,plcg2,phospholipase c gamma 2

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