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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.

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      Acta neuropathologica
      Springer Science and Business Media LLC
      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

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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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          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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            Is Open Access

            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

                Journal
                Acta Neuropathol
                Acta neuropathologica
                Springer Science and Business Media LLC
                1432-0533
                0001-6322
                August 2019
                : 138
                : 2
                Affiliations
                [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.
                Article
                10.1007/s00401-019-02026-8
                10.1007/s00401-019-02026-8
                6660501
                31131421
                a0ec2f65-d495-4851-b706-70c3228afad2
                History

                PLCG2,Parkinson’s disease,Amyotrophic lateral sclerosis,Frontotemporal dementia,Alzheimer’s disease,Progressive supranuclear palsy,Longevity,Phospholipase C Gamma 2,Multiple sclerosis,Dementia with Lewy bodies,Neurodegenerative disease

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