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Meta-Analysis
. 2022 Nov;144(5):821-842.
doi: 10.1007/s00401-022-02454-z. Epub 2022 Sep 6.

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

Iris E Jansen #  1   2   3 , Sven J van der Lee #  4   5   6 , Duber Gomez-Fonseca #  7   8   9 , Itziar de Rojas #  10   11 , Maria Carolina Dalmasso #  12   13 , Benjamin Grenier-Boley #  14 , Anna Zettergren  15 , Aniket Mishra  16 , Muhammad Ali  7   8   9 , Victor Andrade  12   17 , Céline Bellenguez  14 , Luca Kleineidam  12   17   18 , Fahri Küçükali  19   20 , Yun Ju Sung  7   8   9 , Niccolo Tesí  4   5   6 , Ellen M Vromen  4   5 , Douglas P Wightman  21 , Daniel Alcolea  11   22 , Montserrat Alegret  10   11 , Ignacio Alvarez  23   24 , Philippe Amouyel  14 , Lavinia Athanasiu  25 , Shahram Bahrami  25 , Henri Bailly  26 , Olivia Belbin  11   22 , Sverre Bergh  27   28 , Lars Bertram  29 , Geert Jan Biessels  30 , Kaj Blennow  31   32 , Rafael Blesa  11   22 , Mercè Boada  10   11 , Anne Boland  33 , Katharina Buerger  34   35 , Ángel Carracedo  36   37 , Laura Cervera-Carles  11   22 , Geneviève Chene  16   38 , Jurgen A H R Claassen  39   40 , Stephanie Debette  16   38   41 , Jean-Francois Deleuze  33 , Peter Paul de Deyn  42 , Janine Diehl-Schmid  43   44 , Srdjan Djurovic  45   46 , Oriol Dols-Icardo  11   22 , Carole Dufouil  16   47 , Emmanuelle Duron  48 , Emrah Düzel  49   50 ; EADB consortium; Tormod Fladby  51   52 , Juan Fortea  11   22 , Lutz Frölich  53 , Pablo García-González  10   11 , Maria Garcia-Martinez  54 , Ina Giegling  55 , Oliver Goldhardt  43 , Johan Gobom  32 , Timo Grimmer  43 , Annakaisa Haapasalo  56 , Harald Hampel  57   58 , Olivier Hanon  26   59 , Lucrezia Hausner  53 , Stefanie Heilmann-Heimbach  60 , Seppo Helisalmi  61 , Michael T Heneka  17   18 , Isabel Hernández  10   11 , Sanna-Kaisa Herukka  62 , Henne Holstege  4   5   6 , Jonas Jarholm  52 , Silke Kern  15   63 , Anne-Brita Knapskog  64 , Anne M Koivisto  62   65   66 , Johannes Kornhuber  67 , Teemu Kuulasmaa  68 , Carmen Lage  54   69 , Christoph Laske  70   71 , Ville Leinonen  72   73 , Piotr Lewczuk  67   74 , Alberto Lleó  11   22 , Adolfo López de Munain  11   75   76   77 , Sara Lopez-Garcia  54 , Wolfgang Maier  17 , Marta Marquié  10   11 , Merel O Mol  78 , Laura Montrreal  10 , Fermin Moreno  11   75   76 , Sonia Moreno-Grau  10   11 , Gael Nicolas  79 , Markus M Nöthen  60 , Adelina Orellana  10   11 , Lene Pålhaugen  51   52 , Janne M Papma  78 , Florence Pasquier  14 , Robert Perneczky  34   80   81   82 , Oliver Peters  49   83 , Yolande A L Pijnenburg  4   5 , Julius Popp  84   85 , Danielle Posthuma  21 , Ana Pozueta  54 , Josef Priller  83   86   87 , Raquel Puerta  10 , Inés Quintela  36 , Inez Ramakers  88 , Eloy Rodriguez-Rodriguez  54 , Dan Rujescu  55 , Ingvild Saltvedt  89   90 , Pascual Sanchez-Juan  91 , Philip Scheltens  4   5 , Norbert Scherbaum  92 , Matthias Schmid  93 , Anja Schneider  17   18 , Geir Selbæk  28   51   64 , Per Selnes  52 , Alexey Shadrin  25 , Ingmar Skoog  15   63 , Hilkka Soininen  62 , Lluís Tárraga  10   11 , Stefan Teipel  94   95 ; GR@ACE study group; Betty Tijms  4   5 , Magda Tsolaki  96 , Christine Van Broeckhoven  20   97 , Jasper Van Dongen  19   20 , John C van Swieten  78 , Rik Vandenberghe  98   99 , Jean-Sébastien Vidal  26 , Pieter J Visser  4   5   100   101 , Jonathan Vogelgsang  102   103 , Margda Waern  15   104 , Michael Wagner  17   18 , Jens Wiltfang  102   105   106 , Mandy M J Wittens  20   107 , Henrik Zetterberg  31   32   108   109   110 , Miren Zulaica  11   75   76 , Cornelia M van Duijn  111   112 , Maria Bjerke  20   107   113 , Sebastiaan Engelborghs  20   107   113   114 , Frank Jessen  18   115   116 , Charlotte E Teunissen  5   117 , Pau Pastor  118 , Mikko Hiltunen  119 , Martin Ingelsson  120   121   122 , Ole A Andreassen  25   123 , Jordi Clarimón  11   22 , Kristel Sleegers  19   20 , Agustín Ruiz #  10   11 , Alfredo Ramirez #  12   17   18   116   124 , Carlos Cruchaga #  7   8   9 , Jean-Charles Lambert #  14 , Wiesje van der Flier #  125   126
Affiliations
Meta-Analysis

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

Iris E Jansen et al. Acta Neuropathol. 2022 Nov.

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.

Keywords: Alzheimer’s disease; Amyloid-beta; Cerebrospinal fluid; GWAS; Tau.

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Conflict of interest statement

Research programs of Wiesje van der Flier have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, CardioVascular Onderzoek Nederland, Health ~ Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Biogen MA Inc, Boehringer Ingelheim, Life-MI, AVID, Roche BV, Fujifilm, Combinostics. WF holds the Pasman chair. WF is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health ~ Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). WF has performed contract research for Biogen MA Inc, and Boehringer Ingelheim. WF has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), Springer Healthcare. WF is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. WF participated in advisory boards of Biogen MA Inc and Roche. All funding is paid to her institution. WF was associate editor of Alzheimer, Research & Therapy in 2020/2021. WF is associate editor at Brain. CC receives research support from: Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Vivid genetics, Halia Therapeutics and ADx Healthcare. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KBlennow has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. OAA is a consultant to HealthLytix, and received speaker’s honorarium from Lundbeck and Sunovion. SE has served at scientific advisory boards for Biogen, Danone, Eisai, icometrix, Pfizer, Novartis, Nutricia, Roche and has received unrestricted research grants from ADx Neurosciences and Janssen Pharmaceutica. CC receives research support from: Biogen, EISAI, Alector, GSK and Parabon. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Vivid genetics, Halia Therapeutics and ADx Healthcare. HHampel is an employee of Eisai Inc. and serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia; during the past three years he had received lecture fees from Servier, Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics. DA participated in advisory boards from Fujirebio-Europe and Roche Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. OG reports consulting fees from Eli Lilly, grants to his institution from Actelion, and prescreening activities for Julius Clinical/Toyama. ABK has been a PI in the drug trials Roche BN29553, Boehringer-Ingelheim 1346.0023 and is PI in Novo Nordisk NN6535-4730. AL has received personal fees for advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia,Krka Farmacéutica SL, Biogen and Zambon. PSJ has received personal fees for advisory board from Roche Diagnostics and Zambon. GS participated in one advisory board meeting from Biogen. MI is a paid consultant to BioArctic AB. KS is editor at Acta Neuropathologica and associate editor at Alzheimer’s Research & Therapy. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). All other authors declare no financial interests or potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Manhattan plots of the stage 3 GWAS results. a Results visualized for CSFAβ42; b Results visualized for CSF pTau. The y-axes are limited to visualize the non-APOE loci. The lowest P values for APOE are 4.07 × 10–355 and 3.74 × 10–94 for Aβ42 and pTau, respectively
Fig. 2
Fig. 2
LocusZoom plots showing variant association results for a GMNC and b C16orf95 loci. In black, the pTau association signals of this study; and in orange, the lateral ventricular volume (LVV) association signals observed in other studies
Fig. 3
Fig. 3
The effects of all AD-associated loci. The names of the loci are named according to their linked gene names in Bellinguez et al. (2021). Hierarchical clustering was performed on the rows and columns using Eucledian distances and the method ‘average’ for clustering Pathway enrichment analyses was performed on the four first clusters. The enrichment analyses are in Online Resource 1—Table 9. The upper bar shows the odds ratio for AD, where alleles for variants with protective effects have been flipped to show AD-risk increasing effects for all variants. The increases in Aβ42 and pTau (positive Zscores) are shown in red and decreases in AB42 and PTau (negative Z scores) are shown in blue. * = P value < 0.05, X = 0.05 < P value < 0.001, # = 0.001 < P value < 5 × 10–8, $ = P value < 5 × 10–8
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