Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers
Authors: Jansen Iris E , van der Lee Sven J , Gomez-Fonseca Duber , de Rojas Itziar , Dalmasso Maria C , Grenier-Boley Benjamin , Zettergren Anna , Mishra Aniket , Ali Muhammad , Andrade Victor , Bellenguez Céline , Kleineidam Luca , Küçükali Fahri , Sung Yun Ju , Tesí Niccolo , Vromen Ellen M , Wightman Douglas P , Alcolea Daniel , Alegret Montserrat , Alvarez Ignacio , Amouyel Philippe , Andresen Lavinia A , Bahrami Shahram , Bailly Henri , Belbin Olivia , Bergh Sverre , Biessels Geert Jan , Blennow Kaj , Blesa Rafael , Boada Mercè , Boland Anne , Buerger Katharina , Carracedo Ángel , Cervera-Carles Laura , Chene Geneviève , Claassen Jurgen A.H.R. , Debette Stephanie , Deleuze Jean-Francois , de Deyn Peter Paul , Diehl-Schmid Janine , Djurovic Srdjan , Dols-Icardo Oriol , Dufouil Carole , Duron Emmanuelle , Düzel Emrah , Fladby Tormod , Fortea Juan , Frölich Lutz , García-González Pablo , Garcia-Martinez Maria , Giegling Ina , Goldhardt Oliver , Grimmer Timo , Haapasalo Annakaisa , Hampel Harald , Hanon Olivier , Hausner Lucrezia , Heilmann-Heimbach Stefanie , Helisalmi Seppo , Heneka Michael T. , Hernández Isabel , Herukka Sanna-Kaisa , Holstege Henne , Jarholm Jonas , Kern Silke , Knapskog Anne-Brita , Koivisto Anne M. , Kornhuber Johannes , Kuulasmaa Teemu , Lage Carmen , Laske Christoph , Leinonen Ville , Lewczuk Piotr , Lleó Alberto , de Munain Adolfo López , Lopez-Garcia Sara , Maier Wolfgang , Marquié Marta , Mol Merel O. , Montrreal Laura , Moreno Fermin , Moreno-Grau Sonia , Nicolas Gael , Nöthen Markus M , Orellana Adelina , Pålhaugen Lene , Papma Janne , Pasquier Florence , Perneczky Robert , Peters Oliver , Pijnenburg Yolande AL , Popp Julius , Posthuma Danielle , Pozueta Ana , Priller Josef , Puerta Raquel , Quintela Inés , Ramakers Inez , Rodriguez-Rodriguez Eloy , Rujescu Dan , Saltvedt Ingvild , Sanchez-Juan Pascual , Scheltens Philip , Scherbaum Norbert , Schmid Matthias , Schneider Anja , Selbæk Geir , Selnes Per , Shadrin Alexey , Skoog Ingmar , Soininen Hilkka , Tárraga Lluís , Teipel Stefan , Tijms Betty , Tsolaki Magda , Van Broeckhoven Christine , Van Dongen Jasper , van Swieten John C. , Vandenberghe Rik , Vidal Jean-Sébastien , Vogelgsang Jonathan , Waern Margda , Wagner Michael , Wiltfang Jens , Wittens Mandy MJ , Zetterberg Henrik , Zulaica Miren ,   Gra@ce,   EADB, van Duijn Cornelia M. , Bjerke Maria , Engelborghs Sebastiaan , Jessen Frank , Teunissen Charlotte E , Pastor Pau , Hiltunen Mikko , Ingelsson Martin , Andreassen Ole , Clarimón Jordi , Sleegers Kristel , Ruiz Agustín , Ramirez Alfredo , Cruchaga Carlos , Lambert Jean-Charles , van der Flier Wiesje M 
Published: March 2022

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 = 8,074; replication n = 5,042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for amyloid beta 42 (Aβ42) and BIN1 for phosphorylated Tau (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 (amyloid, astrocyte, processing & migration, and migration & motility) 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.