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.
| Original language | English |
|---|---|
| Pages (from-to) | 237-250 |
| Number of pages | 14 |
| Journal | Acta Neuropathologica |
| Volume | 138 |
| Issue number | 2 |
| Early online date | 26 May 2019 |
| DOIs | |
| Publication status | Published - 1 Aug 2019 |
Funding
Acknowledgements The following studies and consortia have contributed to this manuscript. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Sticht-ing VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe): This study/publication is part of the German Research Network on Dementia (KND), the German Research Network on Degenerative Dementia (KNDD; German Study on Ageing, Cognition and Dementia in Primary Care Patients; AgeCoDe), and the Health Service Research Initiative (Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+; AgeQualiDe)) and was funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716; grants Health Service Research Initiative: 01GY1322A, 01GY1322B, 01GY1322C, 01GY1322D, 01GY1322E, 01GY1322F, 01GY1322G). Alfredo Ram-irez was partly supported by the ADAPTED consortium: Alzheimer’s disease Apolipoprotein Pathology for Treatment Elucidation and Development, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. Brain compendium: This work was funded by the UK Medical Research Council (13044). P.F.C. is a Wellcome Trust principal Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.Clinical AD, Sweden: We would like to thank UCL Genomics for performing the genotyping analyses. Danish data: The studies behind the Danish long-lived cases received funding from The National Program for Research Infrastructure 2007 (grant no. 09-063256), the Danish Agency for Science Technology and Innovation, the Velux Foundation, the US National Institute of Health (P01 AG08761), the Danish Agency for Science, Technology and Innovation/The Danish Council for Independent Research (grant no. 11-107308), the European Union’s Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the CERA Foundation (Lyon), the AXA Research Fund, Paris, and The Health Foundation (Helsefonden), Copenhagen, Denmark. The GOYA study was conducted as part of the activities of the Danish Obesity Research Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth Cohort which was established with major funding from the Danish National Research Foundation. Additional support for this cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Fundació ACE (FACE): We would like to thank patients and controls who participated in this project. We are indebted to Trinitat Port-Carbó and her family for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegen-erativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). Agustín Ruiz has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED Grant No. 115975 and by grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-“Una manera de Hacer Europa”), by Fundación bancaria “La Caixa” and Grifols SA (GR@ACE project). Genetics of Healthy Ageing Study (GEHA – NL): The work described in this paper was funded mainly by the EU GEHA Project contract no. LSHM-CT-2004-503-270. Gothenburg Birth Cohort (GBC) Studies: We would like to thank UCL Genomics for performing the genotyping analyses. The studies were supported by The Stena Foundation, The Swedish Research Council (2015-02830, 2013-8717), The Swedish Research Council for Health, Working Life and Wellfare (2013-1202, 2005-0762, 2008-1210, 2013-2300, 2013-2496, 2013-0475), The Brain Foundation, Sahlgrenska University Hospital (ALF), The Alzheimer’s Association (IIRG-03-6168), The Alzheimer’s Association Zenith Award (ZEN-01-3151), Eivind och Elsa K:son Sylvans Stiftelse, The Swedish Alzheimer Foundation. International FTD-Genomics Consortium (IFGC): International FTD-Genomics Consortium (IFGC): The authors thank the IFGC for providing relevant data to support the analyses presented in this manuscript. Further acknowledgments for IFGC (https://ifgcsite.wordpress.com/), e.g. full members list and affiliations, are found in the online supplementary files. IPDGC (The International Parkinson Disease Genomics Consortium): We also would like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). See for a complete overview of members, acknowledgements and funding http:// pdgenetics.org/partners. Kompetenznetz Multiple Sklerose (KKNMS): This work was supported by the German Ministry for Education and Research (BMBF) as part of the “German Competence Network Multiple Sclerosis” (KKNMS) (grant nos. 01GI0916 and 01GI0917) and the Munich Cluster for Systems Neurology (SyNergy). TA was supported by the BMBF through the Integrated Network IntegraMent, under the auspices of the e:Med Programme (01ZX1614J). BH was supported by the EU Horizon 2020 project MultipleMS.Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. Leiden Longevity Study: This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (Sen-terNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (Grant 050-060-810), all in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and by Unilever Colworth.Maria Carolina Dalmasso: Georg Forster Research Award (Alexander von Humboldt Foundation). Mayo Clinic AD, DLB, PD, PSP: We thank the patients and their families for their participation, without whom these studies would not have been possible. Funding for this work was supported by National Institute on Aging [RF AG051504 to NET.; U01 AG046139 to NET]; and National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET; P50 NS072187]. The Mayo Clinic is a Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Information and Referral Center and Center for Advanced Research, NINDS Tau Center without Walls (U54-NS100693) and is supported by Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, the Mangurian Foundation for Lewy body research and NINDS R01 NS078086 (to OAR). The PD program at the Mayo Clinic Florida is also supported by the Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, and The Sol Goldman Charitable Trust. Samples included in this study are from the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP|Society for Progressive Supranuclear Palsy and the Tau Consortium. NDRU cohort: We would like to thank the NIH Neuro Brain Bank for contributing tissue samples; this study was supported in part by grants from the National Institutes of Health: U19-AG03365, P50 NS38377, and P50-AG005146. Tissue samples for genotyping were provided by the Johns Hopkins Morris K. Udall Center of Excellence for Parkinson’s Disease Research (NIH P50 NS38377) and the Johns Hopkins Alzheimer’s Disease Research Center. We aregrateful for the support of the entire BIOCARD study team at Johns Hopkins University. Additionally, we acknowledge the contributions of the Geriatric Psychiatry Branch (GPB) in the intramural program of NIMH who initiated the BIOCARD study. We would like to thank the NIA Baltimore Longitudinal Study of Aging for contributing tissue samples to the Johns Hopkins Alzheimer’s Disease Research Center. DNA panels from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ ninds) were used in this study, as well as clinical data. We thank the following brain banks for providing brain tissues: Banner Sun Health Research Institute, New York Brain Bank, Newcastle Brain Tissue Resource, Human Brain and Spinal Fluid Resource Center, Netherlands Brain Bank Amsterdam, Mount Sinai Brain Bank, Harvard Brain Bank, Duke University Brain Bank, Virginia Commonwealth University Brain Bank, and the Georgetown University Brain Bank. We also thank the following research centers for providing patient samples: University of Michigan, University College London Institute of Neurology, University of Maryland, University of California – San Diego, and University of Miami. We are grateful to members of the North American Brain Expression Consortium for contributing DNA samples. The authors thank the patients and families who have donated DNA samples and brain tissue for scientific research. The research was supported in part by the Intramural Research Program of the NIH National Institute of Neurological Disorders and Stroke and the National Institute on Aging (project numbers: ZIA-NS003154, Z01-AG000949).” Oviedo: This work was partly supported by Grant from Fondo de Investigaciones Sanitarias-Fondos FEDER EuropeanUnion to Victoria Alvarez PI15/00878. Pascual Sánchez-Juan: Pascual Sánchez-Juan is supported by CIBERNED and Carlos III Institute of Health, Spain (PI08/0139, PI12/02288, and PI16/01652), jointly funded by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, “Una manera de hacer Europa”. Project MinE: The ProjectMinE study was supported by the ALS Foundation Netherlands and the MND association (UK) (Project MinE, www.projectmine.com). Risk and modifying factors in Fronto Temporal Dementia (RiMoD-FTD): follows: The SPIN cohort: We are indebted to patients and their families for their participation in the “Sant Pau Initiative on Neurodegeneration cohort”, at the Sant Pau Hospital (Barcelona). This is a multimodal research cohort for biomarker discovery and validation that is partially funded by Generalitat de Catalunya (2017 SGR 547 to JC), as well as from the Institute of Health Carlos III-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-“Una manera de Hacer Europa”) (grants PI11/02526, PI14/01126, and PI17/01019 to JF; PI17/01895 to AL), and the Centro de Investigacion Biomedica en Red Enfermedades Neurodegenerativas programme (Program 1, Alzheimer Disease to AL). We would also like to thank the Fundació Bancària Obra Social La Caixa (DABNI project) to JF and AL; and Fundacion BBVA (to AL), for their support in funding this follow-up study. San Sebastian: We would like to thank patients and control volunteers who participated in this study. We thank Ana Gorostidi for his work at the Biodonostia HRI Genomics Platform. This work was partly supported by CIBERNED. Adolfo López de Munain is supported by Fundación Salud 2000 (PI2013156) and Diputación Foral de Gipuzkoa (Exp. 114/17). UK Biobank analysis: This work was funded by The Netherlands Organization for Scientific Research (NWO VICI 453-14-005). The analyses were carried out on the Genetic Cluster Computer, which is financed by the Netherlands Scientific Organization (NWO: 480-05-003), by the VU University, Amsterdam, The Netherlands, and by the Dutch Brain Foundation, and is hosted by the Dutch National Computing and Networking Services SurfSARA. This research has been conducted using the UK Biobank resource under application number 16406. We are grateful to the numerous participants, researchers, and staff who collected and contributed to the data.
| Funders | Funder number |
|---|---|
| Alzheimer’s disease Apolipoprotein Pathology for Treatment Elucidation and Development | |
| CERA Foundation | |
| Cecilia and Dan Carmichael Family Foundation | |
| Danish Agency for Science, Technology and Innovation/The Danish Council for Independent Research | 11-107308 |
| Dutch Brain Foundation | |
| Dutch National Computing and Networking Services | |
| EU GEHA | LSHM-CT-2004-503-270 |
| EU/EFPIA | PI13/02434, PI16/01861 |
| Eivind och Elsa K:son Sylvans stiftelse | |
| FEDER EuropeanUnion | |
| GEHA | |
| Genetics of Healthy Ageing Study | |
| German Research Network on Degenerative Dementia | |
| German Research Network on Dementia | |
| Health Service Research Initiative | |
| Innovation-Oriented Research Program on Genomics | IGE05007 |
| James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research | |
| KKNMS | 01GI0916, 01GI0917 |
| KND | |
| KNDD | |
| MND association | |
| Mayo Clinic Center for Regenerative Medicine, Mayo Clinic | |
| Mayo Clinic Florida | |
| Munich Cluster for Systems Neurology | 01ZX1614J |
| NIH Neuro Brain Bank | |
| Netherlands Consortium for Healthy Ageing | 050-060-810 |
| Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care | |
| Stena Foundation | |
| Stichting Diorapthe, horstingstuit foundation | |
| Stichting VUmc Fonds | |
| Susan Bass Bolch | |
| Unilever Colworth.Maria | |
| Unión Europea | |
| National Institutes of Health | P50-AG005146, U19-AG03365, P01 AG08761, P50 NS38377 |
| National Institute on Aging | RF AG051504, U01 AG046139 |
| National Institute of Neurological Disorders and Stroke | Z01-AG000949, ZIA-NS003154, P50 NS072187, R01 NS080820, U54-NS100693, R01NS078086 |
| Mayo Clinic | |
| Alzheimer's Association | IIRG-03-6168, ZEN-01-3151 |
| Alexander von Humboldt-Stiftung | |
| American Parkinson Disease Association | |
| Velux Fonden | |
| CurePSP | |
| Wellcome Trust | 212219/Z/18/Z, MC_UU_00015/9 |
| Seventh Framework Programme | 259679 |
| Interreg | |
| Sol Goldman Charitable Trust | |
| Lewy Body Dementia Association | |
| Medical Research Council | 13044 |
| National Institute for Health Research | |
| Health Foundation | |
| University of Cambridge | 09-063256 |
| European Commission | |
| Brain Foundation | |
| Danmarks Grundforskningsfond | |
| Danish Agency for Science and Higher Education | |
| ZonMw | 733050814 |
| Vrije Universiteit Amsterdam | |
| AXA Research Fund | |
| Bundesministerium für Bildung und Forschung | 01GI0714, 01GY1322G, 01GI0713, 01GI0716, 01GY1322E, 01GI0429, 01GI0715, 01GY1322F, 01GI0710, 01GI0423, 01GI0434, 01GI0712, 01GI0711, 01GI0420, 01GI0431, 01GI0422, 01GI0433, 01GI0102, 01GY1322C, 01GY1322D, 01GY1322A, 01GY1322B |
| Generalitat de Catalunya | PI11/02526, PI17/01019, PI14/01126, PI17/01895, 2017 SGR 547 |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 480-05-003, VICI 453-14-005 |
| Vetenskapsrådet | 2013-8717, 2015-02830 |
| Instituto de Salud Carlos III | PI16/01652, PI08/0139, PI12/02288 |
| Fundación Bancaja | |
| Sahlgrenska Universitetssjukhuset | |
| Helsefonden | WT 084762 |
| Forskningsrådet om Hälsa, Arbetsliv och Välfärd | 2013-0475, 2008-1210, 2013-2496, 2013-2300, 2005-0762, 2013-1202 |
| Fundación Salud 2000 | PI2013156 |
| Horizon 2020 | |
| European Regional Development Fund | |
| Alzheimerfonden | |
| Innovative Medicines Initiative | 115975 |
| Alzheimer Nederland | WE09.2014-03 |
| Centre for Medical Systems Biology | |
| Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas | |
| Diputación Foral de Gipuzkoa | 114/17 |
Keywords
- Alzheimer’s disease
- Amyotrophic lateral sclerosis
- Dementia with Lewy bodies
- Frontotemporal dementia
- Longevity
- Multiple sclerosis
- Neurodegenerative disease
- Parkinson’s disease
- Phospholipase C Gamma 2
- PLCG2
- Progressive supranuclear palsy
