Journal article
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
Acta neuropathologica, Vol.138(2), pp.237-250
08/01/2019
DOI: 10.1007/s00401-019-02026-8
PMCID: PMC6660501
PMID: 31131421
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.
Details
- Title: Subtitle
- 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
- Creators
- Sven J van der Lee - Erasmus University RotterdamOlivia J Conway - Mayo Clinic in FloridaIris Jansen - Amsterdam NeuroscienceMinerva M Carrasquillo - Mayo Clinic in FloridaLuca Kleineidam - German Center for Neurodegenerative DiseasesErik van den Akker - Delft University of TechnologyIsabel Hernández - Fundació ACEKristel R van Eijk - University Medical Center UtrechtNajada Stringa - Vrije Universiteit AmsterdamJason A Chen - University of California, Los AngelesAnna Zettergren - University of GothenburgTill F M Andlauer - Max Planck Institute of PsychiatryMonica Diez-Fairen - University Hospital Mútua de TerrassaJavier Simon-Sanchez - University of TübingenAlberto Lleó - Biomedical Research Networking Center on Neurodegenerative DiseasesHenrik Zetterberg - University of GothenburgMarianne Nygaard - University of Southern DenmarkCornelis Blauwendraat - National Institute on AgingJeanne E Savage - Amsterdam NeuroscienceJonas Mengel-From - University of Southern DenmarkSonia Moreno-Grau - Universitat Internacional de CatalunyaMichael Wagner - University Hospital BonnJuan Fortea - Biomedical Research Networking Center on Neurodegenerative DiseasesMichael J Keogh - Newcastle UniversityKaj Blennow - University of GothenburgIngmar Skoog - University of GothenburgManuel A Friese - Competence Network Multiple SclerosisOlga Pletnikova - University Medical CenterMiren Zulaica - Biogipuzkoa Health Research InstituteCarmen Lage - Instituto de Investigación Marqués de ValdecillaItziar de Rojas - Biomedical Research Networking Center on Neurodegenerative DiseasesSteffi Riedel-Heller - Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Leipzig, GermanyIgnacio Illán-Gala - Hospital de Sant PauWei Wei - University of CambridgeBernard Jeune - University of Southern DenmarkAdelina Orellana - Biomedical Research Networking Center on Neurodegenerative DiseasesFlorian Then Bergh - Department of Neurology, University of Leipzig, Leipzig, GermanyXue Wang - Mayo Clinic in FloridaMarc Hulsman - Delft University of TechnologyNina Beker - Amsterdam NeuroscienceNiccolo Tesi - Delft University of TechnologyChristopher M Morris - University of Newcastle AustraliaBegoña Indakoetxea - Biogipuzkoa Health Research InstituteLyduine E Collij - Amsterdam NeuroscienceMartin Scherer - Universität HamburgEstrella Morenas-Rodríguez - Hospital de Sant PauJames W Ironside - University of EdinburghBart N M van Berckel - Amsterdam NeuroscienceDaniel Alcolea - Biomedical Research Networking Center on Neurodegenerative DiseasesHeinz Wiendl - Competence Network Multiple SclerosisSamantha L Strickland - Mayo Clinic in FloridaPau Pastor - Biomedical Research Networking Center on Neurodegenerative DiseasesEloy Rodríguez Rodríguez - IDIVAL, Santander, SpainBradley F Boeve - Mayo ClinicRonald C Petersen - Mayo ClinicTanis J Ferman - Mayo Clinic in FloridaJay A van Gerpen - Mayo Clinic in FloridaMarcel J T Reinders - Delft University of TechnologyRyan J Uitti - Mayo Clinic in FloridaLluís Tárraga - Biomedical Research Networking Center on Neurodegenerative DiseasesWolfgang Maier - University of BonnOriol Dols-Icardo - Hospital de Sant PauAmit Kawalia - University Hospital CologneMaria Carolina Dalmasso - University Hospital CologneMercè Boada - Vall d'Hebron Institut de RecercaUwe K Zettl - University of RostockNatasja M van Schoor - Vrije Universiteit AmsterdamMarian Beekman - Leiden University Medical CenterMariet Allen - Mayo Clinic in FloridaEliezer Masliah - National Institute on AgingAdolfo Lopez de Munain - Biogipuzkoa Health Research InstituteAlexander Pantelyat - Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, 21287, USAZbigniew K Wszolek - Mayo Clinic in FloridaOwen A Ross - Mayo Clinic in FloridaDennis W Dickson - Mayo Clinic in FloridaNeill R Graff-Radford - Mayo Clinic in FloridaDavid Knopman - Mayo ClinicRosa Rademakers - Mayo Clinic in FloridaAfina W Lemstra - Amsterdam NeuroscienceYolande A L Pijnenburg - Vrije Universiteit AmsterdamPhilip Scheltens - Amsterdam UMC Location Vrije Universiteit AmsterdamThomas Gasser - Hertie Institute for Clinical Brain ResearchPatrick F Chinnery - Newcastle UniversityBernhard Hemmer - Munich Cluster for Systems NeurologyMartijn A Huisman - Vrije Universiteit AmsterdamJuan Troncoso - Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USAFermin Moreno - Biomedical Research Networking Center on Neurodegenerative DiseasesEllen A Nohr - University of Southern DenmarkThorkild I A Sørensen - Novo Nordisk FoundationPeter Heutink - Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, GermanyPascual Sánchez-Juan - IDIVAL, Santander, SpainDanielle Posthuma - Vrije Universiteit AmsterdamJordi Clarimón - Biomedical Research Networking Center on Neurodegenerative DiseasesKaare Christensen - University of Southern DenmarkNilüfer Ertekin-Taner - Mayo Clinic in FloridaSonja W Scholz - University Medical CenterAlfredo Ramirez - University Hospital CologneAgustín Ruiz - Fundació ACEEline Slagboom - Leiden University Medical CenterWiesje M van der Flier - Amsterdam University Medical CentersHenne Holstege - Vrije Universiteit AmsterdamTimothy D Griffiths (Contributor) - University of Iowa, Psychological and Brain SciencesDementia Genetics Spanish Consortium (DESGESCO)Alzheimer Disease European DNA biobank (EADB)International FTD-Genomics Consortium (IFGC)International Parkinson Disease Genomics Consortium (IPDGC)Netherlands Brain Bank (NBB)Risk and Modifying factors in Fronto-Temporal Dementia (RiMod-FTD)
- Resource Type
- Journal article
- Publication Details
- Acta neuropathologica, Vol.138(2), pp.237-250
- DOI
- 10.1007/s00401-019-02026-8
- PMID
- 31131421
- PMCID
- PMC6660501
- NLM abbreviation
- Acta Neuropathol
- ISSN
- 0001-6322
- eISSN
- 1432-0533
- Grant note
- WT 084762 / Wellcome Trust K23 AG059891 / NIA NIH HHS Z01 AG000949 / Intramural NIH HHS Wellcome Trust RF1 AG051504 / NIA NIH HHS P01 AG008761 / NIA NIH HHS U54 NS100693 / NINDS NIH HHS ZIA NS003154 / Intramural NIH HHS P50 AG005146 / NIA NIH HHS R01 AG061796 / NIA NIH HHS MC_UU_00015/9 / Medical Research Council 13044 / Medical Research Council EP-C-14-005 / EPA G0900580 / Medical Research Council R01 NS078086 / NINDS NIH HHS P50 NS038377 / NINDS NIH HHS R01 NS080820 / NINDS NIH HHS U01 AG046139 / NIA NIH HHS 212219/Z/18/Z / Wellcome Trust MC_UU_00015/8 / Medical Research Council G1100540 / Medical Research Council P50 NS072187 / NINDS NIH HHS R35 NS097261 / NINDS NIH HHS
- Language
- English
- Date published
- 08/01/2019
- Academic Unit
- Psychological and Brain Sciences
- Record Identifier
- 9984627318302771
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