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

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Abstract

Amyloid-beta 42 (A beta 42) 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 A beta 42 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 A beta 42 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
DOIs
Publication statusE-pub ahead of print - 6 Sep 2022

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© The Author(s) 2022

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