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

2022; Springer Science+Business Media; Volume: 144; Issue: 5 Linguagem: Inglês

10.1007/s00401-022-02454-z

1432-0533

Iris E. Jansen, Sven J. van der Lee, Duber Gomez‐Fonseca, Itziar de Rojas, Carolina Dalmasso, Benjamin Grenier‐Boley, Anna Zettergren, Aniket Mishra, Muhammad Ali, Víctor Andrade, Céline Bellenguez, Luca Kleineidam, Fahri Küçükali, Yun Ju Sung, Niccoló Tesi, Eleonora M. Vromen, Douglas P. Wightman, Daniel Alcolea, Montserrat Alegret, Ignacio Álvarez, Philippe Amouyel, Lavinia Athanasiu, Shahram Bahrami, Henri Bailly, Olivia Belbin, Sverre Bergh, Lars Bertram, Geert Jan Biessels, Kaj Blennow, Rafael Blesa, Merçé Boada, Anne Boland, Katharina Büerger, Ángel Carracedo, Laura Cervera‐Carles, Geneviève Chêne, Jurgen A.H.R. Claassen, Stéphanie Debette, Jean‐François Deleuze, Peter Paul De Deyn, Janine Diehl‐Schmid, Srdjan Djurovic, Oriol Dols‐Icardo, Carole Dufouil, Emmanuelle Duron, Emrah Düzel, Tormod Fladby, Juan Fortea, Lutz Frölich, Pablo García‐González, María García‐Martínez, 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 Hernández, Sanna‐Kaisa Herukka, Henne Holstege, Jonas Alexander Jarholm, Silke Kern, Anne‐Brita Knapskog, Anne M. Koivisto, Johannes Kornhuber, Teemu Kuulasmaa, Carmen Lage, Christoph Laske, Ville Leinonen, Piotr Lewczuk, Alberto Lleó, Adolfo López de Munain, Sara López‐García, Wolfgang Maier, Marta Marquié, Merel O. Mol, Laura Montrreal, Fermín Moreno, Sonia Moreno–Grau, Gaël Nicolas, Markus M. Nöthen, Adelina Orellana, Lene Pålhaugen, Janne M. Papma, Florence Pasquier, Robert Perneczky, Oliver Peters, Yolande A.L. Pijnenburg, Julius Popp, Daniëlle Posthuma, Ana Pozueta, Josef Priller, Raquel Puerta, Inés Quintela, Inez Ramakers, Eloy Rodríguez‐Rodríguez, Dan Rujescu, Ingvild Saltvedt, Pascual Sánchez-Juan, Philip Scheltens, Norbert Scherbaum, Matthias Schmid, Anja Schneider, Geir Selbæk, Per Selnes, Alexey Shadrin, Ingmar Skoog, Hilkka Soininen, Lluís Tárraga, Stefan Teipel, Betty M. Tijms, Magda Tsolaki, Christine Van Broeckhoven, Jasper Van Dongen, John C. van Swieten, Rik Vandenberghe, Jean‐Sébastien Vidal, Pieter Jelle Visser, Jonathan Vogelgsang, Margda Wærn, Michael Wagner, Jens Wiltfang, Mandy Melissa Jane Wittens, Henrik Zetterberg, Miren Zulaica, Cornelia M. van Duijn, Maria Bjerke, Sebastiaan Engelborghs, Frank Jessen, Charlotte E. Teunissen, Pau Pástor, Mikko Hiltunen, Martin Ingelsson, Ole A. Andreassen, Jordi Clarimón, Kristel Sleegers, Agustı́n Ruiz, Alfredo Ramı́rez, Carlos Cruchaga, Jean‐Charles Lambert, Wiesje M. van der Flier,

Genetic Associations and Epidemiology

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.