Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers
Iris E. Jansen(Amsterdam Neuroscience), Sven J. van der Lee(Amsterdam Neuroscience), Duber Gomez‐Fonseca(Washington University in St. Louis), Itziar de Rojas(Instituto de Salud Carlos III), Carolina Dalmasso(Consejo Nacional de Investigaciones Científicas y Técnicas), Benjamin Grenier‐Boley(Inserm), Anna Zettergren(University of Gothenburg), Aniket Mishra(Université de Bordeaux), Muhammad Ali(Washington University in St. Louis), Víctor Andrade(University of Cologne), Céline Bellenguez(Inserm), Luca Kleineidam(University of Cologne), Fahri Küçükali(University of Antwerp), Yun Ju Sung(Washington University in St. Louis), Niccoló Tesi(Amsterdam Neuroscience), Eleonora M. Vromen(Amsterdam Neuroscience), Douglas P. Wightman(Amsterdam Neuroscience), Daniel Alcolea(Universitat Autònoma de Barcelona), Montserrat Alegret(Instituto de Salud Carlos III), Ignacio Álvarez(Mútua Terrassa), Philippe Amouyel(Inserm), Lavinia Athanasiu(University of Oslo), Shahram Bahrami(University of Oslo), Henri Bailly(Université Paris Cité), Olivia Belbin(Universitat Autònoma de Barcelona), Sverre Bergh(Innlandet Hospital Trust), Lars Bertram(University of Lübeck), Geert Jan Biessels(University Medical Center Utrecht), Kaj Blennow(Sahlgrenska University Hospital), Rafael Blesa(Universitat Autònoma de Barcelona), Merçé Boada(Instituto de Salud Carlos III), Anne Boland(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Katharina Büerger(German Center for Neurodegenerative Diseases), Ãngel Carracedo(Universidade de Santiago de Compostela), Laura Cervera‐Carles(Universitat Autònoma de Barcelona), Geneviève Chêne(Université de Bordeaux), Jurgen A.H.R. Claassen(Radboud University Nijmegen), Stéphanie Debette(Boston University), Jean‐François Deleuze(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Peter Paul De Deyn(University Medical Center Groningen), Janine Diehl‐Schmid(TUM Klinikum), Srdjan Djurovic(Oslo University Hospital), Oriol Dols‐Icardo(Universitat Autònoma de Barcelona), Carole Dufouil(Université de Bordeaux), Emmanuelle Duron(Inserm), Emrah Düzel(German Center for Neurodegenerative Diseases), Tormod Fladby(University of Oslo), Juan Fortea(Universitat Autònoma de Barcelona), Lutz Frölich(Heidelberg University), Pablo García‐González(Instituto de Salud Carlos III), María García‐Martínez(Universidad de Cantabria), Ina Giegling(Medical University of Vienna), Oliver Goldhardt(TUM Klinikum), Johan Gobom(Sahlgrenska University Hospital), Timo Grimmer(TUM Klinikum), Annakaisa Haapasalo(University of Eastern Finland), Harald Hampel(Sorbonne Université), Olivier Hanon(Université Paris Cité), Lucrezia Hausner(Heidelberg University), Stefanie Heilmann‐Heimbach(University of Bonn), Seppo Helisalmi(University of Eastern Finland), Michael T. Heneka(University Hospital Bonn), Isabel Hernández(Instituto de Salud Carlos III), Sanna‐Kaisa Herukka(University of Eastern Finland), Henne Holstege(Amsterdam Neuroscience), Jonas Alexander Jarholm(Akershus University Hospital), Silke Kern(Sahlgrenska University Hospital), Anne‐Brita Knapskog(Oslo University Hospital), Anne M. Koivisto(University of Eastern Finland), Johannes Kornhuber(Friedrich-Alexander-Universität Erlangen-Nürnberg), Teemu Kuulasmaa(University of Eastern Finland), Carmen Lage(Universidad de Cantabria), Christoph Laske(German Center for Neurodegenerative Diseases), Ville Leinonen(University of Eastern Finland), Piotr Lewczuk(Medical University of Białystok), Alberto Lleó(Universitat Autònoma de Barcelona), Adolfo López de Munain(University of the Basque Country), Sara López‐García(Universidad de Cantabria), Wolfgang Maier(University Hospital Bonn), Marta Marquié(Instituto de Salud Carlos III), Merel O. Mol(Erasmus MC), Laura Montrreal(Fundació ACE), Fermín Moreno(Instituto de Salud Carlos III), Sonia Moreno–Grau(Instituto de Salud Carlos III), Gaël Nicolas(Inserm), Markus M. Nöthen(University of Bonn), Adelina Orellana(Instituto de Salud Carlos III), Lene Pålhaugen(University of Oslo), Janne M. Papma(Erasmus MC), Florence Pasquier(Inserm), Robert Perneczky(German Center for Neurodegenerative Diseases), Oliver Peters(German Center for Neurodegenerative Diseases), Yolande A.L. Pijnenburg(Amsterdam Neuroscience), Julius Popp(University of Zurich), Daniëlle Posthuma(Amsterdam Neuroscience), Ana Pozueta(Universidad de Cantabria), Josef Priller(German Center for Neurodegenerative Diseases), Raquel Puerta(Fundació ACE), Inés Quintela(Universidade de Santiago de Compostela), Inez Ramakers(Maastricht University), Eloy Rodríguez‐Rodríguez(Universidad de Cantabria), Dan Rujescu(Medical University of Vienna), Ingvild Saltvedt(Norwegian University of Science and Technology), Pascual Sánchez‐Juan(Instituto de Salud Carlos III), Philip Scheltens(Amsterdam Neuroscience), Norbert Scherbaum(University of Duisburg-Essen), Matthias Schmid(University Hospital Bonn), Anja Schneider(University Hospital Bonn), Geir Selbæk(Oslo University Hospital), Per Selnes(Akershus University Hospital), Alexey Shadrin(University of Oslo), Ingmar Skoog(Sahlgrenska University Hospital), Hilkka Soininen(University of Eastern Finland), Lluís Tárraga(Instituto de Salud Carlos III), Stefan Teipel(German Center for Neurodegenerative Diseases), The GR@ACE study group(Amsterdam Neuroscience), Betty M. Tijms(Aristotle University of Thessaloniki), Magda Tsolaki(University of Antwerp), Christine Van Broeckhoven(University of Antwerp), Jasper Van Dongen(University of Antwerp), John C. van Swieten(Erasmus MC), Rik Vandenberghe(Université Paris Cité), Jean‐Sébastien Vidal(Université Paris Cité), Pieter Jelle Visser(Karolinska Institutet), Jonathan Vogelgsang(Harvard University), Margda Wærn(Sahlgrenska University Hospital), Michael Wagner(University Hospital Bonn), Jens Wiltfang(University of Antwerp), Mandy Melissa Jane Wittens(Vrije Universiteit Brussel), Henrik Zetterberg(Sahlgrenska University Hospital), Miren Zulaica(Instituto de Salud Carlos III), Cornelia M. van Duijn(University of Antwerp), Maria Bjerke(Vrije Universiteit Brussel), Sebastiaan Engelborghs(Vrije Universiteit Brussel), Frank Jessen(University of Cologne), Charlotte E. Teunissen(Amsterdam Neuroscience), Pau Pástor(University of Eastern Finland), Mikko Hiltunen(Uppsala University), Martin Ingelsson(Uppsala University), Ole A. Andreassen(Universitat Autònoma de Barcelona), Jordi Clarimón(Universitat Autònoma de Barcelona), Kristel Sleegers(University of Antwerp), Agustı́n Ruiz(Instituto de Salud Carlos III), Alfredo Ramı́rez(University of Cologne), Carlos Cruchaga(Inserm), Jean‐Charles Lambert(Inserm), Wiesje M. van der Flier(Amsterdam Neuroscience)
Cited by 135Open Access
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.
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