Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Iris E. Jansen*, Sven J. van der Lee, Duber Gomez-Fonseca, Itziar de Rojas, Maria Carolina Dalmasso, Benjamin Grenier-Boley, Anna Zettergren, Aniket Mishra, Muhammad Ali, Victor Andrade, Celine Bellenguez, Luca Kleineidam, Fahri Kucukali, Yun Ju Sung, Niccolo Tesi, Ellen M. Vromen, Douglas P. Wightman, Daniel Alcolea, Montserrat Alegret, Ignacio AlvarezPhilippe Amouyel, Lavinia Athanasiu, Shahram Bahrami, Henri Bailly, Olivia Belbin, Sverre Bergh, Lars Bertram, Geert Jan Biessels, Kaj Blennow, Rafael Blesa, Merce Boada, Anne Boland, Katharina Buerger, Angel Carracedo, Laura Cervera-Carles, Genevieve Chene, Jurgen A. H. R. Claassen, Stephanie Debette, Jean-Francois Deleuze, Peter Paul de Deyn, Janine Diehl-Schmid, Srdjan Djurovic, Oriol Dols-Icardo, Carole Dufouil, Emmanuelle Duron, Emrah Duezel, Tormod Fladby, Juan Fortea, Lutz Froelich, Pablo Garcia-Gonzalez, Maria Garcia-Martinez, Ina Giegling, Oliver Goldhardt, Johan Gobom, Timo Grimmer, Annakaisa Haapasalo, Harald Hampel, Olivier Hanon, Lucrezia Hausner, Stefanie Heilmann-Heimbach, Seppo Helisalmi, Michael T. Heneka, Isabel Hernandez, Sanna-Kaisa Herukka, Henne Holstege, Jonas Jarholm, Silke Kern, Anne-Brita Knapskog, Anne M. Koivisto, Johannes Kornhuber, Teemu Kuulasmaa, Carmen Lage, Christoph Laske, Ville Leinonen, Piotr Lewczuk, Alberto Lleo, Adolfo Lopez de Munain, Sara Lopez-Garcia, Wolfgang Maier, Marta Marquie, Merel O. Mol, Laura Montrreal, Fermin Moreno, Sonia Moreno-Grau, Gael Nicolas, Markus M. Nothen, Adelina Orellana, Lene Palhaugen, Janne M. Papma, Florence Pasquier, Robert Perneczky, Oliver Peters, Yolande A. L. Pijnenburg, Julius Popp, Danielle Posthuma, Ana Pozueta, Josef Priller, Raquel Puerta, Ines Quintela, Inez Ramakers, Eloy Rodriguez-Rodriguez, Dan Rujescu, Ingvild Saltvedt, Pascual Sanchez-Juan, Philip Scheltens, Norbert Scherbaum, Matthias Schmid, Anja Schneider, Geir Selbaek, Per Selnes, Alexey Shadrin, Ingmar Skoog, Hilkka Soininen, Lluis Tarraga, Stefan Teipel, Betty Tijms, Magda Tsolaki, Christine Van Broeckhoven, Jasper Van Dongen, John C. van Swieten, Rik Vandenberghe, Jean-Sebastien Vidal, Pieter J. Visser, Jonathan Vogelgsang, Margda Waern, Michael Wagner, Jens Wiltfang, Mandy M. J. Wittens, Henrik Zetterberg, Miren Zulaica, Cornelia M. van Duijn, Maria Bjerke, Sebastiaan Engelborghs, Frank Jessen, Charlotte E. Teunissen, Pau Pastor, Mikko Hiltunen, Martin Ingelsson, Ole A. Andreassen, Jordi Clarimon, Kristel Sleegers, Agustin Ruiz, Alfredo Ramirez, Carlos Cruchaga, Jean-Charles Lambert, Wiesje van der Flier

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

Original languageEnglish
Pages (from-to)821-842
Number of pages22
JournalActa Neuropathologica
Volume144
Issue number5
Early online date6 Sept 2022
DOIs
Publication statusPublished - Nov 2022

Bibliographical note

Funding Information:
This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Programme, Neurodegenerative Disease Research (JPND). 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 Stichting 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).Part of the work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI was part of and funded by the Dutch Federation of University Medical Centers and has received initial funding from the Dutch Government (from 2007-2011). Since 2020, this work was carried out in the context of Parelsnoer clinical biobanks at Health-RI ( https://www.health-ri.nl/initiatives/parelsnoer ). Part of the genotyping included in this work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Alfredo Ramirez is also supported by the German Research Foundation (DFG) grants Nr: RA 1971/6-1, RA1971/7-1, and RA 1971/8-1. We would like to thank patients and controls who participated in this project. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria ‘La Caixa’, Fundació ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)–Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER–‘Una manera de hacer Europa’). The position held by I.dR. is funded by grant. FI20/00215. PFIS Contratos Predoctorales de Formación en Investigación en Salud. We would like to thank UCL Genomics, London, UK, for performing the genotyping analyses of the samples within the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444, and P01AG003991. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenomics.wustl.edu/)and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Research at the Belgian EADB site is funded in part by the Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund. The work of Valdecilla was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigación Sanitario, PI08/0139, PI12/02288, PI16/01652, and PI20/01011), the JPND (DEMTEST PI11/03028), the CIBERNED, and the Siemens Healthineers. We thank the Valdecilla Biobank (PT17/0015/0019), integrated into the Spanish Biobank Network, for their support and collaboration in sample collection and management. Our heartfelt thanks to the participants of the Valdecilla Cohort for their generosity. The work of ADGEN was supported by EU Joint Programme—Neurodegenerative Disease Research (301220) and the Academy of Finland (338182). The DELCODE study (Study-ID:BN012 ) was supported and conducted by the German Center for Neurodegenerative Diseases (DZNE). The data samples were provided by the DELCODE study group. Details and participating sites can be found at www.dzne.de/en/research/studies/clinical-studies/delcode . The German Dementia Competence Network (KND) is funded by the German Federal Ministry of Education and Research (BMBF) grants Number: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711. WF, SvdL, HHolstege, CT and PhS are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD ( www.aboard-project.nl ). ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds and Gieskes-Strijbisfonds. IEJ was partially supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). AZ was supported by the Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361), and the Dementia Foundation (2020-04-13, 2021-04-17). ISk was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALF 716681), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496), Swedish Brain Power, Hjärnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019- 0163), the Alzheimer's Association Zenith Award (ZEN-01-3151), the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159), the Alzheimer's Association (IIRG-03-6168, IIRG-09-131338) and the Bank of Sweden Tercentenary Foundation. SK was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALF GBG-771071), the Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825), and the Swedish Research Council (2019-02075). MW was supported by the Swedish Research Council 2016-01590. DP was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB was supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG068398-01), and the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495). CC receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614), and the Chuck Zuckerberg Initiative (CZI).

Funding Information:
Research programs of Wiesje van der Flier have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, CardioVascular Onderzoek Nederland, Health ~ Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Biogen MA Inc, Boehringer Ingelheim, Life-MI, AVID, Roche BV, Fujifilm, Combinostics. WF holds the Pasman chair. WF is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health ~ Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). WF has performed contract research for Biogen MA Inc, and Boehringer Ingelheim. WF has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), Springer Healthcare. WF is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. WF participated in advisory boards of Biogen MA Inc and Roche. All funding is paid to her institution. WF was associate editor of Alzheimer, Research & Therapy in 2020/2021. WF is associate editor at Brain. CC receives research support from: Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Vivid genetics, Halia Therapeutics and ADx Healthcare. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KBlennow has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. OAA is a consultant to HealthLytix, and received speaker’s honorarium from Lundbeck and Sunovion. SE has served at scientific advisory boards for Biogen, Danone, Eisai, icometrix, Pfizer, Novartis, Nutricia, Roche and has received unrestricted research grants from ADx Neurosciences and Janssen Pharmaceutica. CC receives research support from: Biogen, EISAI, Alector, GSK and Parabon. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Vivid genetics, Halia Therapeutics and ADx Healthcare. HHampel is an employee of Eisai Inc. and serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia; during the past three years he had received lecture fees from Servier, Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics. DA participated in advisory boards from Fujirebio-Europe and Roche Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. OG reports consulting fees from Eli Lilly, grants to his institution from Actelion, and prescreening activities for Julius Clinical/Toyama. ABK has been a PI in the drug trials Roche BN29553, Boehringer-Ingelheim 1346.0023 and is PI in Novo Nordisk NN6535-4730. AL has received personal fees for advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia,Krka Farmacéutica SL, Biogen and Zambon. PSJ has received personal fees for advisory board from Roche Diagnostics and Zambon. GS participated in one advisory board meeting from Biogen. MI is a paid consultant to BioArctic AB. KS is editor at Acta Neuropathologica and associate editor at Alzheimer’s Research & Therapy. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). All other authors declare no financial interests or potential conflicts of interest.

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