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

EADB consortium; The GR@ACE study group

doi:10.1007/s00401-022-02454-z

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

EADB consortium
, The GR@ACE study group

Research output: Contribution to journal › Article › peer-review

80 Scopus citations

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 language	English
Pages (from-to)	821-842
Number of pages	22
Journal	Acta Neuropathologica
Volume	144
Issue number	5
DOIs	https://doi.org/10.1007/s00401-022-02454-z
State	Published - Nov 2022

Keywords

Alzheimer’s disease
Amyloid-beta
Cerebrospinal fluid
GWAS
Tau

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10.1007/s00401-022-02454-z

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@article{2ee301b46ef84dbd9ea4cb1dd1a96d0b,

title = "Genome-wide meta-analysis for Alzheimer{\textquoteright}s disease cerebrospinal fluid biomarkers",

abstract = "Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer{\textquoteright}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.",

keywords = "Alzheimer{\textquoteright}s disease, Amyloid-beta, Cerebrospinal fluid, GWAS, Tau",

author = "\{EADB consortium\} and \{The GR@ACE study group\} and Jansen, \{Iris E.\} and \{van der Lee\}, \{Sven J.\} and Duber Gomez-Fonseca and \{de Rojas\}, Itziar and Dalmasso, \{Maria Carolina\} and Benjamin Grenier-Boley and Anna Zettergren and Aniket Mishra and Muhammad Ali and Victor Andrade and C{\'e}line Bellenguez and Luca Kleineidam and Fahri K{\"u}{\c c}{\"u}kali and Sung, \{Yun Ju\} and Niccolo Tes{\'i} and Vromen, \{Ellen M.\} and Wightman, \{Douglas P.\} and Daniel Alcolea and Montserrat Alegret and Ignacio Alvarez and Philippe Amouyel and Lavinia Athanasiu and Shahram Bahrami and Henri Bailly and Olivia Belbin and Sverre Bergh and Lars Bertram and Biessels, \{Geert Jan\} and Kaj Blennow and Rafael Blesa and Merc{\`e} Boada and Anne Boland and Katharina Buerger and {\'A}ngel Carracedo and Laura Cervera-Carles and Genevi{\`e}ve Chene and Claassen, \{Jurgen A.H.R.\} and Stephanie Debette and Deleuze, \{Jean Francois\} and \{de Deyn\}, \{Peter Paul\} and Janine Diehl-Schmid and Srdjan Djurovic and Oriol Dols-Icardo and Carole Dufouil and Emmanuelle Duron and Emrah D{\"u}zel and Tormod Fladby and Juan Fortea and Lutz Fr{\"o}lich and Pablo Garc{\'i}a-Gonz{\'a}lez and Maria Garcia-Martinez and Ina Giegling and Oliver Goldhardt and Johan Gobom and Timo Grimmer and Annakaisa Haapasalo and Harald Hampel and Olivier Hanon and Lucrezia Hausner and Stefanie Heilmann-Heimbach and Seppo Helisalmi and Heneka, \{Michael T.\} and Isabel Hern{\'a}ndez and Herukka, \{Sanna Kaisa\} and Henne Holstege and Jonas Jarholm and Silke Kern and Knapskog, \{Anne Brita\} and Koivisto, \{Anne M.\} and Johannes Kornhuber and Teemu Kuulasmaa and Carmen Lage and Christoph Laske and Ville Leinonen and Piotr Lewczuk and Alberto Lle{\'o} and \{de Munain\}, \{Adolfo L{\'o}pez\} and Sara Lopez-Garcia and Wolfgang Maier and Marta Marqui{\'e} and Mol, \{Merel O.\} and Laura Montrreal and Fermin Moreno and Sonia Moreno-Grau and Gael Nicolas and N{\"o}then, \{Markus M.\} and Adelina Orellana and Lene P{\aa}lhaugen and Papma, \{Janne M.\} and Florence Pasquier and Robert Perneczky and Oliver Peters and Pijnenburg, \{Yolande A.L.\} and Julius Popp and Danielle Posthuma and Ana Pozueta and Josef Priller and Raquel Puerta and In{\'e}s Quintela and Inez Ramakers and Eloy Rodriguez-Rodriguez and Dan Rujescu and Ingvild Saltvedt and Pascual Sanchez-Juan and Philip Scheltens and Norbert Scherbaum and Matthias Schmid and Anja Schneider and Geir Selb{\ae}k and Per Selnes and Alexey Shadrin and Ingmar Skoog and Hilkka Soininen and Llu{\'i}s T{\'a}rraga and Stefan Teipel and Betty Tijms and Magda Tsolaki and \{Van Broeckhoven\}, Christine and \{Van Dongen\}, Jasper and \{van Swieten\}, \{John C.\} and Rik Vandenberghe and Vidal, \{Jean S{\'e}bastien\} and Visser, \{Pieter J.\} and Jonathan Vogelgsang and Margda Waern and Michael Wagner and Jens Wiltfang and Wittens, \{Mandy M.J.\} and Henrik Zetterberg and Miren Zulaica and \{van Duijn\}, \{Cornelia M.\} and Maria Bjerke and Sebastiaan Engelborghs and Frank Jessen and Teunissen, \{Charlotte E.\} and Pau Pastor and Mikko Hiltunen and Martin Ingelsson and Andreassen, \{Ole A.\} and Jordi Clarim{\'o}n and Kristel Sleegers and Agust{\'i}n Ruiz and Alfredo Ramirez and Carlos Cruchaga and Lambert, \{Jean Charles\} and \{van der Flier\}, Wiesje",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = nov,

doi = "10.1007/s00401-022-02454-z",

language = "English",

volume = "144",

pages = "821--842",

journal = "Acta Neuropathologica",

issn = "0001-6322",

number = "5",

}

TY - JOUR

T1 - Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

AU - EADB consortium

AU - The GR@ACE study group

AU - Jansen, Iris E.

AU - van der Lee, Sven J.

AU - Gomez-Fonseca, Duber

AU - de Rojas, Itziar

AU - Dalmasso, Maria Carolina

AU - Grenier-Boley, Benjamin

AU - Zettergren, Anna

AU - Mishra, Aniket

AU - Ali, Muhammad

AU - Andrade, Victor

AU - Bellenguez, Céline

AU - Kleineidam, Luca

AU - Küçükali, Fahri

AU - Sung, Yun Ju

AU - Tesí, Niccolo

AU - Vromen, Ellen M.

AU - Wightman, Douglas P.

AU - Alcolea, Daniel

AU - Alegret, Montserrat

AU - Alvarez, Ignacio

AU - Amouyel, Philippe

AU - Athanasiu, Lavinia

AU - Bahrami, Shahram

AU - Bailly, Henri

AU - Belbin, Olivia

AU - Bergh, Sverre

AU - Bertram, Lars

AU - Biessels, Geert Jan

AU - Blennow, Kaj

AU - Blesa, Rafael

AU - Boada, Mercè

AU - Boland, Anne

AU - Buerger, Katharina

AU - Carracedo, Ángel

AU - Cervera-Carles, Laura

AU - Chene, Geneviève

AU - Claassen, Jurgen A.H.R.

AU - Debette, Stephanie

AU - Deleuze, Jean Francois

AU - de Deyn, Peter Paul

AU - Diehl-Schmid, Janine

AU - Djurovic, Srdjan

AU - Dols-Icardo, Oriol

AU - Dufouil, Carole

AU - Duron, Emmanuelle

AU - Düzel, Emrah

AU - Fladby, Tormod

AU - Fortea, Juan

AU - Frölich, Lutz

AU - García-González, Pablo

AU - Garcia-Martinez, Maria

AU - Giegling, Ina

AU - Goldhardt, Oliver

AU - Gobom, Johan

AU - Grimmer, Timo

AU - Haapasalo, Annakaisa

AU - Hampel, Harald

AU - Hanon, Olivier

AU - Hausner, Lucrezia

AU - Heilmann-Heimbach, Stefanie

AU - Helisalmi, Seppo

AU - Heneka, Michael T.

AU - Hernández, Isabel

AU - Herukka, Sanna Kaisa

AU - Holstege, Henne

AU - Jarholm, Jonas

AU - Kern, Silke

AU - Knapskog, Anne Brita

AU - Koivisto, Anne M.

AU - Kornhuber, Johannes

AU - Kuulasmaa, Teemu

AU - Lage, Carmen

AU - Laske, Christoph

AU - Leinonen, Ville

AU - Lewczuk, Piotr

AU - Lleó, Alberto

AU - de Munain, Adolfo López

AU - Lopez-Garcia, Sara

AU - Maier, Wolfgang

AU - Marquié, Marta

AU - Mol, Merel O.

AU - Montrreal, Laura

AU - Moreno, Fermin

AU - Moreno-Grau, Sonia

AU - Nicolas, Gael

AU - Nöthen, Markus M.

AU - Orellana, Adelina

AU - Pålhaugen, Lene

AU - Papma, Janne M.

AU - Pasquier, Florence

AU - Perneczky, Robert

AU - Peters, Oliver

AU - Pijnenburg, Yolande A.L.

AU - Popp, Julius

AU - Posthuma, Danielle

AU - Pozueta, Ana

AU - Priller, Josef

AU - Puerta, Raquel

AU - Quintela, Inés

AU - Ramakers, Inez

AU - Rodriguez-Rodriguez, Eloy

AU - Rujescu, Dan

AU - Saltvedt, Ingvild

AU - Sanchez-Juan, Pascual

AU - Scheltens, Philip

AU - Scherbaum, Norbert

AU - Schmid, Matthias

AU - Schneider, Anja

AU - Selbæk, Geir

AU - Selnes, Per

AU - Shadrin, Alexey

AU - Skoog, Ingmar

AU - Soininen, Hilkka

AU - Tárraga, Lluís

AU - Teipel, Stefan

AU - Tijms, Betty

AU - Tsolaki, Magda

AU - Van Broeckhoven, Christine

AU - Van Dongen, Jasper

AU - van Swieten, John C.

AU - Vandenberghe, Rik

AU - Vidal, Jean Sébastien

AU - Visser, Pieter J.

AU - Vogelgsang, Jonathan

AU - Waern, Margda

AU - Wagner, Michael

AU - Wiltfang, Jens

AU - Wittens, Mandy M.J.

AU - Zetterberg, Henrik

AU - Zulaica, Miren

AU - van Duijn, Cornelia M.

AU - Bjerke, Maria

AU - Engelborghs, Sebastiaan

AU - Jessen, Frank

AU - Teunissen, Charlotte E.

AU - Pastor, Pau

AU - Hiltunen, Mikko

AU - Ingelsson, Martin

AU - Andreassen, Ole A.

AU - Clarimón, Jordi

AU - Sleegers, Kristel

AU - Ruiz, Agustín

AU - Ramirez, Alfredo

AU - Cruchaga, Carlos

AU - Lambert, Jean Charles

AU - van der Flier, Wiesje

PY - 2022/11

Y1 - 2022/11

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - Amyloid-beta

KW - Cerebrospinal fluid

KW - GWAS

KW - Tau

UR - https://www.scopus.com/pages/publications/85137914762

U2 - 10.1007/s00401-022-02454-z

DO - 10.1007/s00401-022-02454-z

M3 - Article

C2 - 36066633

AN - SCOPUS:85137914762

SN - 0001-6322

VL - 144

SP - 821

EP - 842

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 5

ER -

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

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Keywords

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